The Interplay Between Obesity and Aging in Breast Cancer and Regulatory Function of MicroRNAs in This Pathway

Abstract

Breast cancer (BC) is a significant contributor to cancer-related deaths in women, and it has complex connections with obesity and aging. This review explores the interaction between obesity and aging in relation to the development and progression of BC, focusing on the controlling role of microRNAs (miRNAs). Obesity, characterized by excess adipose tissue, contributes to a proinflammatory environment and metabolic dysregulation, which are important in tumor development. Aging, associated with cellular senescence and systemic changes, further exacerbates these conditions. miRNAs, small noncoding RNAs that regulate gene expression, play key roles in these processes, impacting pathways involved in cell proliferation, apoptosis, and cancer metastasis, either as tumor suppressors or oncogenes. Importantly, specific miRNAs are implicated in mediating the impact of obesity and aging on BC. Exploring the regulatory networks controlled by miRNAs provides valuable information on new targets for therapy and predictive markers, demonstrating the potential for using miRNA-based interventions to treat BC in obese and elderly individuals. This review emphasizes the importance of integrated research strategies to understand the complex connections between obesity, aging, and miRNA regulation in BC.

Introduction

Breast cancer (BC) is the second most common and deadly form of malignancy in women (Bodai and Tuso, 2015). Approximately 0.5–1% of the male population develops BC, as reported by the World Health Organization (WHO). The incidence rate of BC is the highest of all cancers, with a prevalence of 11.7% in 2020, representing a total of 2,261,419 cases. The mortality rate associated with BC has also experienced a remarkable increase and will be 6.9% in 2020, corresponding to 684,996 deaths (Sung et al., 2021; WHO, 2021). In addition, 2.3 million women will be diagnosed with BC, with a staggering 685,000 people succumbing to the disease worldwide (Cozzo et al., 2017). Nations with a high level of economic development have a higher proportion of BC deaths. It is predicted that by 2040, the number of new BC cases diagnosed each year will exceed 3 million, resulting in more than 1 million deaths per year (Arnold et al., 2022). BC is classified into different subtypes based on the presence or absence of certain protein receptors, such as human epidermal growth factor receptor 2 (HER2), progesterone receptor (PR), and estrogen receptor (ER). The presence or absence of these receptors plays a critical role in the prognosis and metastatic potential of the disease. Triple-negative BC (TNBC), in which none of those above receptors are expressed, is associated with the poorest prognosis and the highest likelihood of metastasis compared with other BC subtypes (Nagini, 2017). BC is a complex disease caused by several factors (Zendehdel et al., 2018). Several factors, including genetic predisposition and hereditary characteristics, can influence the risk of developing this disease. Moreover, the number of endogenous hormones may also play a role: Reproductive factors, exogenous hormone use, lifestyle, anthropometric characteristics, mammographically proven increased breast density, and the presence of benign breast disease may influence the risk of BC (Pashayan et al., 2020). Meta-analyses have revealed a 30% increased risk of recurrence or mortality in obese women diagnosed with BC compared with women of normal weight (Protani et al., 2010). Obesity is a distinct risk element for various types of cancer, encompassing including BC (Argolo et al., 2018; Protani et al., 2010). The prevalence of obesity has increased over the past five decades, reaching pandemic proportions (Yanovski, 2018). The worldwide prevalence of obesity increased from 0.9% to 7.8% in women and from 0.7% to 5.6% in men between 1975 and 2016 (Elkhawaga et al., 2023). Aging is a pervasive biological phenomenon that leads to a gradual and irreversible deterioration of physical performance in all body systems and remains one of the most influential factors in predicting BC incidence (Freedman et al., 2018; Oblak et al., 2021). This decline is initiated by the buildup of damage as a result of exposure to various stress factors (Northrop, 1925). The process of aging is recognized as a major contributor to pathological conditions, including malignant neoplasms, cardiovascular disease, diabetes, and neurodegenerative disorders (van Schooneveld et al., 2015). The diagnosis of the majority of BCs does not develop until after age 55 (Cruz-Reyes and Radisky, 2023). A plausible way to understand the increasing propensity for early onset of BC is to recognize the importance of accelerated biological maturation in susceptibility to BC. Biological maturation is characterized by the gradual deterioration of functions, commonly known as the basic features of senescence. The decline of these factors increases susceptibility to disease illness and mortality (Lemoine, 2021; López-Otín et al., 2013).

The relationship between obesity and aging in BC development is complex and involves various molecular mechanisms. Obesity and aging work together to promote BC through shared pathways, including chronic inflammation, insulin resistance (IR), and hormonal imbalances. Increased fat in older adults results in a state of chronic inflammation marked by heightened levels of proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). This ongoing inflammation creates conditions that facilitate DNA damage and genomic instability, which are critical for cancer development (Boutas et al., 2023). Elevated insulin levels and IR stimulate the PI3K/AKT (phosphatidylinositol 3-kinase/protein kinase B) and MAPK (mitogen-activated protein kinase) signaling pathways, advancing oncogenic activities. Excessive insulin and IGF-1 (insulin-like growth factor 1) can amplify ER signaling, particularly significant in hormone receptor-positive BC common in postmenopausal women (Zhang et al., 2021a). Adipokines, including leptin and adiponectin, play a role in regulating estrogen production in adipose tissue, thus impacting cancer risk (Booth et al., 2012).

Studies conducted recently have indicated that the relationship between getting older and being obese in relation to BC is regulated by the presence of different microRNAs (miRNAs) (Atoum et al., 2020; Rakib et al., 2022). miRNAs are a category of small, endogenous RNAs that are typically 20–22 nucleotides in length. Their main function is to repress gene expression by selectively binding to messenger RNAs, resulting in either their cleavage or inhibition of translation. The formation of miRNAs occurs through the process of loading miRNA onto the effector protein ARGONAUTE, which subsequently performs various cellular functions (Lei et al., 2021). Aberrant regulation of miRNA expression has been linked to the progression and growth of various types of malignancies, such as BC (Shah and Chen, 2014).

In this article, we present current knowledge about the regulatory role of miRNAs in aging and obesity cross talk in BC and also the therapeutic potential of these miRNAs.

Aging and Obesity as Risk Factors for BC

Aging is a complex phenomenon caused by various factors and is characterized by the progressive deterioration or decline of functionality at all levels of the human organism (López-Otín et al., 2013). Tumors found in people older than 55 years often show reduced aggressiveness, with increased incidence in older women leading to the highest overall number of BC-related deaths (Cruz-Reyes and Radisky, 2023). Numerous factors contribute to the initiation of the aging process, such as telomere dysfunction or DNA damage (He and Sharpless, 2017; Schumacher et al., 2021), oxidase stress (Harraan, 1955), and inflammation (inflamm-aging) (Franceschi et al., 2017; Franceschi et al., 2000).

In mammalian organisms, the telomere consists of tandem repeats of TTAGGG located in the terminal region of each chromosome. This specific arrangement performs the important task of protecting the chromosome from potential DNA damage and ensuring that it remains isolated from neighboring chromosomes (Muraki et al., 2012). Telomere length measurement in surrogate tissues such as mononuclear cells, buccal cells, peripheral blood lymphocytes, and white blood cells (WBCs) is seen as a reliable biomarker for assessing susceptibility to BC (Iwasaki et al., 2008; Levy et al., 1998). Gradual telomeres occur during the period of cell division in human somatic cells. This phenomenon ultimately leads to telomere dysfunction, chromosome instability, and the onset of cellular senescence, apoptosis, and the aging process in humans (Jafri et al., 2016).

The immune system is one of the most important initial barriers to the development and progression of BC (Yarmarkovich et al., 2020). The aging process is accompanied by a decrease in the functionality of the immune system, commonly referred to as immunosenescence. Immunosenescence is characterized by the occurrence of a chronic, low-grade inflammatory response, a decreased ability and response to new antigens, and a higher likelihood of autoimmune responses (Goronzy and Weyand, 2013). Immunosenescence and inflammatory aging pose a significant challenge to the ability of tissues to prevent neoplasia transformation and progression advancement by releasing chemokines that promote tumor growth, facilitate infiltration of immunosuppressive cells, and promote proliferation of age-mixed leukocytes whose antitumor immune activities have declined in the tissue microenvironment (Coppé et al., 2010; Fulop et al., 2013; Lian et al., 2020; Pawelec, 2007).

Reactive oxygen species (ROS) are diminutive compounds originating from oxygen, manifesting as free radicals with one or more unpaired electrons (Li et al., 2016). Biologically significant species include the superoxide anion radical, the hydroxyl radical, and hydrogen peroxide (Finkel, 2011). In addition, inflammation favors the generation of ROS, characterized as free radicals, ions, or molecules with unpaired electrons (Snezhkina et al., 2019). When the level of ROS is elevated, it can cause damage and lead to the development of genetic instability and tumor formation (Liou and Storz, 2010). ROS, in conjunction with the inflammatory response, are capable of influencing various mechanisms that contribute to the progression of cancers such as BC (Seyfried and Huysentruyt, 2013).

Two percent of individuals diagnosed with BC were obese as evidenced by a research study showing that obesity increases susceptibility to developing BC (Buttros et al., 2013). Obesity is known to trigger hyperinsulinemia (Prakash, 2018), the overexpression of leptin, and the downregulation of adiponectin (Mauvais-Jarvis et al., 2013), as well as an increase in estradiol levels through the process of aromatization. In addition, the presence of IGF-1 is also observed in obese individuals (Taroeno-Hariadi et al., 2021).

Leptin, as a predominant mediator in the association of obesity and BC, plays a central role in tumor development, progression, enlargement, and dissemination (Barone et al., 2016). In patients with BC, an association can be observed between leptin levels, ER, and PR expression. Previous studies have also demonstrated a physiological mechanism by which estradiol levels enhance the expression of leptin mRNA in adipose tissue and promote an increase in the expression of leptin and leptin receptors in BC cell lines (Catalano et al., 2004; Naimo et al., 2020; Tewari et al., 2022). In addition to its endocrine functions, leptin also exhibits some preoncogenic mitogenic effects via the LEPR receptor (LEPR leptin receptor), which is abundant in BC cells. Leptin triggers the activation of PI3K/AKT and JAK/STAT (Janus kinase/signal transducer and activator of transcription proteins) signaling pathways, ultimately leading to the stimulation of cell proliferation (Gui et al., 2017). Although the mechanisms of inhibition of cancer cell apoptosis and induction of expression of antiapoptotic genes such as bax (Bcl-2–associated X protein), bak (Bcl-2 homologous antagonist/killer), and angiogenesis by VEFG (vascular endothelial growth factor) receptor production are widely recognized, there is conflicting evidence on the effects of leptin on BC susceptibility (Gui et al., 2017). Leptin-induced epithelial–mesenchymal transition (EMT) is characterized by alterations in cell–cell contact and the promotion of an elongated morphological shape. EMT refers to the ability of epithelial cells to transition from a polarized morphology to a more relaxed mesenchymal phenotype, thereby facilitating the progression of cancer metastases (Thiery, 2002). Adiponectin appears to act in a manner opposite to leptin. The adiponectin/leptin ratio is commonly used in the literature to describe their interaction (Lyu et al., 2022). The ratio of adiponectin to leptin is reduced in the adipose tissue of individuals who are obese (Simone et al., 2016). Low serum adiponectin levels have been associated with a high risk of BC, while high serum levels may be protective against it (Georgiou et al., 2016; Gu et al., 2018). Adiponectin acts as a defense against tumor progression via its major receptors, namely AdipoR1 and AdipoR2. In addition, it is known for its ability to stimulate cellular apoptosis by facilitating adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) signaling while interfering with the PI3K/AKT signaling pathway (Lyu et al., 2022; Nehme et al., 2022; Tsankof and Tziomalos, 2022).

Glucose intolerance, a metabolic abnormality that occurs in patients in the early stages of cancer, leads to the development of a diabetic state resembling type 2 diabetes and is characterized by IR (Argiles and Lopez-Soriano, 2001; Tayek, 1992). This hyperinsulinemia condition is related to the body mass index (BMI) (Leung et al., 2000). The synthesis and manifestation of proinflammatory adipocytokines, namely TNF-α, IL-6, and monocyte chemoattractant protein 1, are increased in individuals with obesity and IR (Sartipy and Loskutoff, 2003). IR is a common pathological situation in obese patients with impaired insulin movement in adipose tissue. In the course of IR, the insulin level in the bloodstream is significantly increased to avoid hyperglycemia (Guo et al., 2015). Higher BMI confirmed better irritation and IR ranges in females with BC (Ruan et al., 2023).

The Interplay Between Aging, Obesity, and BC

Obesity and aging have long been recognized as important factors that increase the risk of BC (Buttros et al., 2013; Richman et al., 2023). Based on the available studies, it has been found that the breast is one of the vulnerable tissues of the body as we age. It should also be mentioned that with age, the amount of fatty acids and the mass of body fat tissue increase (Ou et al., 2022). Aged adipose tissue with factors such as the significant increase in cytokines and chemokines (Xu et al., 2015), endothelial dysfunction (Donato et al., 2014), decrease in blood vessels and tissue fibrosis, and other metabolic changes in AT with increasing age along with increased IR (Das et al., 2004) may cause cancer (Pérez et al., 2016). The correlation between increasing obesity rates and increasing cancer rates cannot be ignored (Bhupathiraju and Hu, 2016). In addition to the aging population, the prevalence of obesity also contributes to the cancer burden in society (Qiang et al., 2020).

These factors highlight why understanding the interactions between aging and obesity, and their role in BC development, is crucial for prevention and treatment strategies. The interaction between aging, obesity, and BC is mediated by several molecular mechanisms, with miRNA regulation, playing a crucial role in BC development.

Overview of miRNA and Its Role in Regulating Gene Expression

miRNAs, despite their noncoding nature, are essential participants in posttranscriptional gene regulation. These short RNAs play a central role in the control gene expression (He and Hannon, 2004). They bind to target RNAs, resulting in either translational blockage or degradation, ultimately leading to the suppression of gene expression (Bartel, 2004). The role of miRNAs is essential for various cellular activities in both normal biological processes and diseases. Dysregulation or dysfunction of these miRNAs can have serious consequences, including the development of cancer. In addition, it is worth noting that their involvement in multiple signaling pathways highlights the broad spectrum of functions of miRNAs (Alberti and Cochella, 2017; Schraml and Grillari, 2012). The understanding of miRNAs in regulating gene expression is currently being developed in view of new novel therapies (Arif et al., 2020).

The Role of miRNAs in Obesity-Related BC

It has been suggested that there is a link between obesity and cancer via miRNAs. Research studies have indicated that a common biological element between obesity and BC may be the modulation of specific miRNAs, either by upregulation or downregulation (Kasiappan and Rajarajan, 2017). miRNAs play a crucial role in controlling essential signaling pathways associated with adipogenesis, lipid storage in adipocytes, metabolic processes, and secretion of adipokines. They accomplish this by affecting the genes responsible for the production of proteins involved in signal transduction and transcriptional regulation (Ahonen et al., 2021). In addition, miRNAs also affect inflammation (Martínez-Gutierrez et al., 2022), IR (Kasiappan et al., 2014), and sex hormone regulation (Liu et al., 2019). The signaling pathways that are controlled in this matter include RAS/RAF/MAPK, JAK/STAT3, TGF-β (transforming growth factor-beta), PTEN (phosphatase and tensin homolog deleted on chromosome 10), PI3K/AKT, PPAR-γ (peroxisome proliferator-activated receptor gamma), leptin pathway, TRAF6 (TNF receptor-associated factor 6), Bcl-2 (B cell leukemia/lymphoma 2 protein), SIRT1 (sirtuin 1), Notch1 (neurogenic locus notch homolog protein 1), p53, IGF, IGF 1R/WNT 1/β catenin, AKT/ERK (extracellular signal-regulated kinase), EMT pathway, MAP3K8/ERK1/2/PPAR-γ, AMPKα/autophagy pathway, GLUT 1 (glucose transporter protein type 1) expression, and TCA cycle activity. Table 1 describes the types of miRNAs involved in the regulation of obesity-related BC pathways.

Table 1.

Types of MicroRNAs That Are Involved in Regulating Obesity-Related Breast Cancer Pathways

MicroRNAs(miRNAs)	Mechanisms of breast cancer (BC) related to obesity	Target genes and pathways	Details	References
Let-7	Adipogenesis, insulin resistance	PBX3-Hmga2, CCND2, c-MYC, K-RAS, H-RAS, HMGA2, CDC34, PPAR-γ, C/EBP RAS/RAF/MAPK JAK-STAT-3 insulin, TGF-β superfamily, IGF, and Wnt/catenin	The miRNA that is commonly perceived as a tumor suppressor is widely acknowledged. It is observed to be downregulated in various cancer types, including BC. This particular miRNA is responsible for regulating the tumorigenicity of BC cells. Additionally, it plays a crucial role in regulating adipogenesis when studied in vitro. In females, the presence of Let-7b is indicative of insulin resistance, regardless of the presence of obesity. Furthermore, the overexpression of Let-7 in murine models has been linked to impaired glucose tolerance.	Duggan et al., 2022; Kasiappan and Rajarajan, 2017
miRNA-21	Adipogenesis, inflammation, sex hormones, leptin	PDCD4, PTEN, CDC25, MSH2, MESPIN -TGFBR2, Ap1, PPAR-γ, C/EBP STAT3, TGF-β, PTEN inhibition, PI3K/Akt activation, STAT3 (indirectly by IL-6) attach with TLR7/8 on macrophages	The process of proliferation, metastasis, and epithelial–mesenchymal transition (EMT) is facilitated by miR-21. In addition, it plays a role in promoting adipogenesis, specifically the formation of fat cells. The activation of miR-21 is attributed to STAT3 and NF-κB. Furthermore, it is frequently upregulated in solid tumors but downregulated by estradiol. The increase in adipogenesis in human adipose tissue-derived stromal cells is due to the modulation of TGF-β and the targeting of STAT3 signaling by miR-21. The PPAR-γ signaling pathway interacts with these two signaling pathways. When BC cells are exposed to oxidized Low Density Lipoprotein (LDL), which mimics a hyperlipidemic condition, it leads to inflammation and proliferation signaling through the overexpression of miR-21. Moreover, the excessive upregulation of miR-21 leads to the suppression of PTEN and the initiation of AKT phosphorylation. The induction of miR-21 is triggered by leptin, consequently enhancing the release of IL-6, a cytokine known for its proinflammatory properties. IL-6 then triggers STAT3 to facilitate the transcriptional activation of both miR-21 and miR-181-b1.	Duggan et al., 2022; Hanusek et al., 2022; Kasiappan and Rajarajan, 2017; Olivieri et al., 2021; Taroeno-Hariadi et al., 2021
miRNA-30a/c	Adipogenesis, sex hormones	MTDH-PDCD4, PTEN, CDC25, MSH2, MESPIN-TWF1, IL-11-PAI-1, ALK2 SERPINE1, SERBP1B3, ALK2, DRP1, p53, EMT, UBC9, ITGB3, AVEN, RUNX2 MTDH, ZEB2 BLOCKS KRAS/MAPK PATHWAY	The promotion of drug sensitivity is accompanied by the promotion of adipogenesis. Conversely, the inhibition of adipogenesis is achieved through inhibition. Additionally, the inhibitory effects on apoptosis are observed due to the inhibition of p53. Furthermore, inhibition is known to impede the proliferation and metastasis of cells, which is evident in the lower levels observed in primary breast tumors compared with normal tissues. The expression of miR-30c is positively correlated with ERα levels but negatively correlated with EGFR levels in BC patients. High expression of miR-30 is associated with improved survival rates in BC patients and also enhances the susceptibility of cell lines to chemotherapy. The miR30c-MAML-YAP/TAZ axis plays a crucial role in regulating the nuclear localization of YAP/TAZ downstream of the Hippo signaling pathway, which, in turn, contributes to maintaining tissue homeostasis and suppressing tumor formation. Additionally, a signaling axis involving p53, miR-30a, and ZEB2 has been identified to control the aggressiveness of triple-negative BC.	Duggan et al., 2022; Kasiappan and Rajarajan, 2017
miRNA-30	Adipogenesis	PPAR-γ, C/EBP, STAT1 TGF-β superfamily, Wnt/catenin, IGF, and insulin	The adipogenesis process, which involves the expression of various genes, transcription factors (PPAR-γ, C/EBP), and multiple signaling pathways (Wnt/catenin, TGF-β superfamily, insulin, and IGF), as well as the extracellular matrix, is the target of investigation. While multiple miRNAs may target identical genes, a single miRNA could also potentially regulate a variety of different target genes, thus playing a crucial role in BC associated with obesity. miR-30 acts on the transcription factor STAT1 to hinder the activity of IFN-γ. Moreover, it facilitates the differentiation of adipocytes by targeting plasminogen activator inhibitor (PAI-1) and activin receptor-like kinase 2 (ALK2). The downregulation of miR-30a occurs in obese adipocytes. In the context of BC, miR-30 suppresses cyclin E2, leading to cell cycle arrest.	Olivieri et al., 2021
miRNA-31	Adipogenesis, leptin	RHOA, RADIXIN, IGA5, PRKCE-C/ebpa, PPAR-γ TGF-β superfamily, Wnt/catenin, IGF, and insulin	Promotes drug sensitivity and inhibits metastasis, inhibits adipogenesis, leptin-induced miR-31.	Olivieri et al., 2021; Kasiappan and Rajarajan, 2017
miRNA-93	Adipogenesis	LATS2-Sirt7, TBX3	Promotes angiogenesis and metastasis, promotes fat mass and insulin resistance	Kasiappan and Rajarajan, 2017
miRNA-124	Adipogenesis	SLUG, EZH2, ROCK2, CDK4-CREB	Inhibits metastasis, promotes adipogenesis.	Kasiappan and Rajarajan, 2017
miRNA-143	Adipogenesis, leptin	DNMT3-Erk5, HER3, Mapk7 ERK5, FNDC38, HK, ADD3, ELK1, KLF5, FOP2A, PLK1, PRC1, KRAS, BCL2, MDM2, PRC1, MAPK7, DNMT3A, MAPK12, COL1A, COL5A3, ERK5, BBC3 BCL2, SURVIVIN PTEN hypermethylation, PPAR-γ, AP2, increase AKT1, TNFRS F10c methylation, PPAR-γ, leptin pathway, TGF-β superfamily, Wnt/catenin, IGF, and insulin	It slows down the growth and spread of cells. It slows down the development of fat cells. The activity of this gene is controlled by mTOR signaling. It has beneficial effects in stopping the development of tumors by decreasing the activity of hexokinase in a controlled environment. It slows down the growth of BC tumors by reducing the activity of BCL-2, ERK5, and KRAS oncogenes. When there is an excessive amount of it, it halts the proliferation of cells induced by E₂. There is a higher level of expression in normal breast tissue compared with cancerous tissue. miR-143 is known to enhance the differentiation of premature fat cells, affecting PPAR-γ and stopping ERK5. ERK, which is a part of MAPK, aids in cell growth, forming new blood vessels, cell development, and staying alive. Despite not playing a role in fat cell development, ERK5 is important in predicting the outcome of BC. Leptin decreases the level of miR-143.	Kasiappan and Rajarajan, 2017; Duggan et al., 2022; Olivieri et al., 2021; Taroeno-Hariadi et al., 2021
miRNA-155	Adipogenesis, inflammation, IR	RHOA, CXCR4, SOX1, p53, FOXO3-C/EBPβ PPAR-γ	Adipocyte differentiation and the brown adipocyte-like phenotype are both inhibited by it. In obese adipocytes with inflammation, miR-155 is overexpressed, and this is consistent with NF-κB activity. This is likely a result of its capability to target PPAR-γ. The targeting of SOC1 and MMP6 by miR-155 is what leads to the promotion of BC cell proliferation.	Hanusek et al., 2022; Kasiappan and Rajarajan, 2017; Taroeno-Hariadi et al., 2021
miRNA-181a	Adipogenesis	ATM-TNF-α	Promotes angiogenesis and metastasis, promotes adipocyte differentiation.	Kasiappan and Rajarajan, 2017
miRNA-221/222	Adipogenesis, IR	ER-α, PTEN, p57, p27-CDKN1B, GLUT4, inhibit the PTEN and p27 (Chen et al.) proteins, resulting in decreased insulin-induced enhancement of glucose uptake. This inhibition also leads to the downregulation of MYC by inhibiting lncRNA GAS5 and activating Akt, ultimately promoting proliferation, cell cycle progression, and cell survival through the increase of ER-α	The process of adipogenesis involves the regulation of various gene expressions, transcription factors (such as PPAR-γ and C/EBP), and multiple signaling pathways (including Wnt/β-catenin, TGF-β superfamily, IGF, and insulin), in conjunction with the extracellular matrix. A recent investigation conducted by Li et al. identified an increase in miR221/222 levels in females diagnosed with type 2 diabetes mellitus and postmenopausal BC. The upregulation of miR221/222 contributes to inflammation within adipose tissue and decreases insulin sensitivity through its interaction with ERα and GLUT4. In BC, miR-222 suppresses PTEN and p27Kip1, activates Akt, inhibits lncRNA GAS5, and modulates MYC.	Kasiappan and Rajarajan, 2017; Olivieri et al., 2021
miRNA-302b	Adipogenesis	c-Myc, RUNX2 PI3K/AKT signaling	In BC cells cocultured with immature adipocytes, miR-302b sustains SOX2 and c-MYC expression, leading to the development of cytokine-induced cancer stem cell-like characteristics. Meanwhile, in BC, miR-302b directly affects RUNX2, which is a stimulator of the PI3K/AKT signaling pathway.	Taroeno-Hariadi et al., 2021; Zhao et al., 2016
miRNA-326	Adipogenesis	ABCC1-C/ebpa	Promotes drug sensitivity, inhibits adipogenesis.	Kasiappan and Rajarajan, 2017
miRNA-335	Adipogenesis	SOX4, TENASCIN c, SP1, BCL-2-RUNX2, PPAR-γ, C/EBP, TGF-β superfamily, Wnt/catenin IGF, and insulin	Induces apoptosis and inhibits metastasis, promotes adipogenesis.	Kasiappan and Rajarajan, 2017
miRNA-146a/b	Adipogenesis, Inflammation	TRAF6, NF-κB, IRAK1, EGFR, BRCA1, KLF7, SIRT (TRAF)-6	MDA-MB-231 cell function is diminished through the downregulation of NF-κB, leading to a decrease in the expression of NF-κB target genes such as IL-8, IL-6, and MMP-9. The introduction of miR-146a into MDA-MB-231 cells impedes their invasion and migration in laboratory settings, as well as the spread of BC in living organisms. The upregulation of miR-146a/b by FOXP3 negatively affects the growth of BC cells by promoting programmed cell death. In BC cells, the activation of miR-146a/b by BRMS1 results in the suppression of invasion and migration, as well as reduced metastasis in living organisms. The growth of visceral preadipocytes is restrained and their specialization is encouraged. Additionally, miR-146b plays a critical role in the anti-inflammatory effects of adiponectin by reducing the expression of TNF-α and IL-1β through the inhibition of TNF receptor-associated factor (TRAF)-6 signaling, a crucial mediator in the production of various proinflammatory cytokines regulated by the NF-κB pathway.	Benbaibeche et al., 2022; Duggan et al., 2022; Gerasymchuk et al., 2020; Wani et al., 2021
miRNA-210	Adipogenesis	E-cadherin and HIF1-α, Wnt	Adipogenesis is encouraged through the suppression of Wnt signaling. In cases of BC, it is activated by hypoxic conditions and works against E-cadherin and HIF1-α.	Taroeno-Hariadi et al., 2021
miRNA-27b	IR, leptin	FOXO1, ST14, SPRY1, FOXO1, BAK, CBLB/GRB2, PPAR-γ, PI3K-signaling, and Wnt1	miR-27 levels are increased in obesity because of low oxygen levels in the body. Blocking the miR-27 family affects the function of PPAR-γ, triggers Wnt1 signaling, and ultimately inhibits GLUT-4 and PI3K signaling, causing insulin resistance, high blood sugar, and high levels of fats in the blood. In BC, miR-27 functions as a tumor suppressing miR.	Taroeno-Hariadi et al., 2021
miRNA-24-3p	Adipogenesis, sex hormones	HMGCR, SR-B1, DHCR24 and p27Kip1, Bim, SREBP2	The overexpression of miR-24-3p due to obesity leads to the inhibition of scavenger receptor B-1 (SRB1), resulting in reduced HDL uptake, lipid metabolism, and intake of steroid hormones. The increased expression of miR-24-3p inhibits p27Kip1 and Bim, promoting the growth and proliferation of BC.	Liu et al., 2019; Taroeno-Hariadi et al., 2021
miRNA-34a	Inflammation, insulin resistant, leptin	Suppressing the development of adipose tissue inflammation induced by macrophage M2 can be achieved by inhibiting antiapoptotic factors such as CCND1, BCL2, MYC, CDK6, E2F3, and SIRT1 Wnt/β, BCL-2, SIRT1, Notch1	The increased expression of miR-34a in the adipose tissue of individuals who are overweight or obese is associated with insulin resistance and inflammation related to metabolism. Exosomes, which are small vesicles released by mature adipocytes containing lipids, carry miR-34a to macrophages. Within macrophages, miR-34a inhibits the M2 phenotype, which has anti-inflammatory properties, by suppressing Krüppel-like factor 4 (Klf-4). miR-34a is a key player in exacerbating the systemic inflammation and metabolic imbalances associated with obesity. Conversely, studies have shown that miR-34a is downregulated in breast tissue. Acting as a tumor suppressor, miR-34a reduces the activity of target genes, including BCL-2, SIRT1, Notch1, as well as genes involved in the Wnt/β-catenin signaling pathway such as fra-1 and MYC. The presence of the leptin antagonist honokiol (HNK) leads to an increase in miR-34a levels.	Atoum et al., 2020; Taroeno-Hariadi et al., 2021
miRNA-34	Adipogenesis	FGFR1, SIRT 1 p53 is under direct transcriptional regulation by miR-34.SIRT1 and Bcl-2 downregulation	BC cell growth is inhibited by miR-34. White Adipose Tissue (WAT) browning is suppressed by miR-34, which has a direct impact on adipocyte differentiation, adiposity, and metabolism. The compound in question selectively aims at FGFR1 (fibroblast growth factor receptor 1) and SIRT1 (sirtuin 1). The reduction in SIRT1 levels is linked with the compromised control of gene expression of brown and beige markers by means of the deacetylation of PPARGC1-a.	Heyn et al., 2020
miRNA-34b	Sex hormones	Increase of JAG1	The activation of estrogen downregulates miR-34b in MCF-7 cells. This leads to the expression of miR-34b target genes, resulting in an increase in JAG1 and subsequently inducing cell proliferation.	Hanusek et al., 2022; Jones et al., 2019; Kasiappan et al., 2014
miRNA-210	Adipogenesis	PPAR-γ, C/EBP, STAT1 E-cadherin, HIF1-α TGF-β superfamily, Wnt/catenin, IGF, and insulin	The adipogenesis process is the target, involving a variety of gene expression, transcription factors (such as PPAR-γ and C/EBP), several signaling pathways (including TGF-β superfamily, Wnt/catenin, IGF, and insulin), and the extracellular matrix. Many miRNAs may target the same genes, although a single miRNA may also have the ability to modulate multiple target genes, playing a vital role in obesity-related BC. miR-30 restricts the action of IFN-γ by targeting the transcription factor STAT1. Moreover, it enhances the differentiation of adipocytes through the regulation of plasminogen activator inhibitor (PAI-1) and activin receptor-like kinase 2 (ALK2). The downregulation of miR-30a is observed in adipocytes of obese individuals. Within the realm of BC, miR-30 functions to inhibit cyclin E2, resulting in the arrest of the cell cycle. miR-210 plays a role in promoting adipogenesis by inhibiting Wnt signaling and in BC, it is induced under hypoxic conditions leading to the targeting of E-cadherin and HIF1-α.	Kasiappan and Rajarajan, 2017; Müller et al., 2014; Olivieri et al., 2021
miRNA‐3184‐5p	The regulation of cancer cell growth and spread is overseen by miR‐3184‐5p	The FOXP4–NOTCH pathway induced the proliferation of MABC cells through the EMT pathway. This led to the proliferation of MABC cells through the induced EMT pathway	In a coculture of mature adipocyte BC cell, the upregulation of miR3184-5p targets FOXP4- NOTCH and induces the EMT pathway. In contrast, the downregulation of miR-1881c-3p reduces the inhibition of PPAR-γ, which, in turn, stimulates the proliferation of BC cells.	Taroeno-Hariadi et al., 2021
miRNA-9-5p	Adipogenesis, adiponectin	PPAR-γ and C/EBP, ADIPOQ, Wnt/β-catenin, Wnt/β-catenin PPAR-γ	BC miR-9-5p downregulates Wnt3a′s 3′UTR, thereby inhibiting Wnt/β-catenin signaling and facilitating mesenchymal stem cell (MSC) differentiation into adipocytes. Furthermore, miR-9-5p promotes the expression of adipogenesis-related genes such as adipsin, PPAR-γ, and C/EBPα in MSCs. Importantly, bioinformatic and luciferase assays revealed that miR-9-5p exerts a negative regulatory effect on the antitumoral gene ADIPOQ.	Hanusek et al., 2022; Li et al., 2022
miRNA-125	Adipogenesis	Wnt/β-catenin, E-cadherin, HIF1-α, HER2, VEGF. HDAC4/5, HER3, HUR, EPOR, ENPEP, CK-a, HER2, RhoA, and MMP11	BCBC miR-125 functions as a tumor suppressor in BC by downregulating oncogenes such as HER2 and VEGF. Its diminished expression in obesity-related BC correlates with poor clinical outcomes due to obesity-induced inflammatory cytokines like TNF-α reducing miR-125 levels, thereby enhancing tumor growth and angiogenesis. miR-125a-5p reduces proliferation by targeting HDAC4/5, HER3, and HUR genes, whereas miR-125b promotes proliferation via EPOR, ENPEP, CK-a, and HER2. It suppresses cell proliferation, invasion, and metastasis. In this context, the expression of these miRNAs is reduced. miR-125a-3p and miR-125b-3p enhance adipogenesis by targeting RhoA and MMP11, respectively. Furthermore, these miRNAs exhibit increased expression in favorable cancer conditions.	Olivieri et al., 2021; Kasiappan and Rajarajan, 2017
miRNA-15a	Adipogenesis, Inflammation	PPAR-γ, C/EBP, STAT1, NF-κB TGF-β superfamily, Wnt/catenin, IGF, and insulin	The process of adipogenesis involves the expression of various genes, transcription factors (such as PPAR-γ and C/EBP), multiple signaling pathways (including TGF-β superfamily, Wnt/catenin, IGF, and insulin), and the extracellular matrix. Many miRNAs can target the same genes, and a single miRNA has the ability to modulate numerous target genes, thus playing a significant role in obesity-related BC. No studies have been published so far regarding the suppression of miR-15a in the context of low-grade chronic inflammation associated with obesity.	Kasiappan and Rajarajan, 2017, Olivieri et al., 2021, Gerasymchuk et al., 2020
miRNA-181c-3p	Adipogenesis, leptin	PPAR-α,the growth and spread of cancer cells are controlled by it	After coculture with MA, overexpression leads to reduced proliferation and invasion of BC cells stimulated by adipocytes. Leptin-induced BC cells show decreased expression of miR-181c-3p. Nevertheless, piperine treatment reverses the downregulation of miR-181c-3p induced by leptin in both BC cells. Upregulation of miR-181c-3p enhances inhibition of PPAR-α, thus decreasing cell migration and proliferation in leptin-induced BC cells.	Hanusek et al., 2022; Rajarajan et al., 2021
miRNA-144	Adipogenesis	Downregulates activity of MAP3K8/ERK1/2/PPAR-γ	Promotes tumor advancement by modifying energy metabolism, resulting in the development of brown/beige-like traits in mature adipocytes.	Hanusek et al., 2022
miRNA-126	IRS1	The activation of the IRS1 led to the activation of the phosphor-AMPKα/autophagy pathway and resulted in the stabilization of HIF1α expression in adipocytes	Facilitates tumor progression by altering energy metabolism.	Hanusek et al., 2022
miRNA-22	Adipogenesis	GLUT 1 expression downregulating PKM2 inhibiting ACLY expression	The expression of GLUT 1 is inversely related to miRNA 22, which restricts glucose uptake in nontumor cells. Lowering invasiveness could be achieved by increasing proliferation.	Hanusek et al., 2022
miRNA-137	Adipogenesis	Increasing TCA cycle activity (indirectly)	Increase glutamine uptake and survival of cancer cells.	Hanusek et al., 2022
miRNA-105	Adipogenesis	Influence CAFs to regulate c-Myc	Increase in glutaminolysis and glycolysis.	Hanusek et al., 2022
miR-21-5p	Inflammation	Downregulation of the Wnt/β-catenin	Increased proinflammatory cytokine (IL-1β and IL-22) expression and cancer growth and invasiveness.	Hanusek et al., 2022
miRNA 191	Estrogen	Estrogen decreases the expression of DAB2 and increases the expression of miRNA 191 (as oncomiR)	The promotion of cell proliferation of ER BC cells in vitro was a result of this.	Hanusek et al., 2022
miRNA-34b	Estrogen	Increase of JAG1	miR-34b expression is downregulated in MCF-7 cells due to estrogenic activation. This downregulation leads to an increase in JAG1 and subsequently induces cell proliferation by targeting miR-34b genes.	Hanusek et al., 2022
miRNA-1271	Estrogen	Targets SNAI2	The activation of tumor suppressor miR-1271, which targets SNAI2 and inhibits the EMT in BC cells, suggests that ERα-E2 may have an antitumor effect. The depletion of ERα can lead to BC metastasis, partly due to its antagonistic role in the EMT process signaling.	Hanusek et al., 2022

ABCC1-C/ebpa, Adenosine triphosphate binding cassette subfamily C member 1/CCAAT/enhancer binding protein beta; ACLY, ATP citrate lyase; ADD3, Adducin 3; ALK2, anaplastic lymphoma kinase; ATM-Tnf-a, ataxia telangiectasia mutated Tumor necrosis factor alpha; AVEN, Apoptosis And Caspase Activation Inhibitor; AKT, Serine/Threonine Kinase; Ap1, Activator protein 1; BAK, BCL2 Antagonist/Killer; BCL2, B cell lymphoma protein 2; BRCA1, Breast Cancer gene 1; BRMS1, breast cancer metastasis suppressor 1; Blm, Bcl-2-like protein; C/EBP, CCAAT/enhancer binding protein; CAFs, cancer-associated fibroblast; CBLB, Cbl proto-oncogene B; CCND2, cyclin D2; CDC34, Cell Division Cycle 34; CDK4, Cyclin Dependent Kinase; CDKN1B, Cyclin-dependent Kinase Inhibitor 1B; COL1A, Collagen, type I, alpha 1,; CREB, CAMP responsive element binding protein; CXCR4, C-X-C chemokine receptor type 4; DAB2, Disabled-2; DHCR24, 24-dehydrocholesterol reductase; DNMT3, DNA methyltransferase 3; DRP1, dynamin-related protein 1; E2F3, Early region 2 binding factor; EGFR, epidermal growth factor receptor; ELK1, ETS Transcription Factor ELK1; EMT, Epithelial–mesenchymal transition; ER alpha, Estrogen receptor alpha; EZH2, Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit; Erk5, Mitogen-activated protein kinase 1 (MAPK 1); FGFR1, Fibroblast growth receptor 1; FNDC38, Fibronectin Type III Domain Containing 38; FOP2A, Forkhead box protein P2; FOXO1, Forkhead box O1 transcription factor-1; FOXP4, Forkhead Box P4; GLUT4, Glucose transporter type 4; GRB2, Growth factor receptor bound protein 2; H-RAS, Hras Harvey Rat sarcoma virus oncogene; HER3, human epidermal growth factor receptor 3; HIF1-a, Hypoxia-Inducible Factor 1alpha; HK, Hexokinase; HMGCR, hydroxy-3-methylglutaryl-coenzyme A reductase; Hmga2, High Mobility Group AT-Hook 2; IFN-γ, Interferon-gamma; IGA5, Immunoglobulin heavy constant alpha; IGF, serum insulin like growth factor; IL-6, Interleukin 6; IRAK1, Interleukin-1 receptor-associated kinase 1; IRS1, Insulin receptor substrate 1; ITGB3, Integrin Subunit Beta 3; IncRNA, Long noncoding RNAs; JAG1, aged Canonical Notch; JAK/STAT, Janus kinase/signal transducers and activators of transcription; K-RAS, Kristen Rat Sarcoma Viral oncogene homolog; LATS2, Hippo pathway kinase large tumor suppressor 2; Ligand 1 KLF5, Kruppel-like factor 5; MAPK, Mitogen activated protein kinases; MDM2, Mouse Double minute 2 homolog; MMP6, matrix metallopeptidase 6; MSH2, DNA mismatch repair protein; MTDH, Metadherin; NF-?B, Nuclear factor kappa-light-chain-enhancer of activated B cells; Notch1, Neurogenic locus notch homolog protein 1; PAI-1, Plasminogen activator inhibitor-1; PBX3, Pre-B-cell leukemia transcription factor 3; PDCD4, Programmed Cell Death 4; PI3K/Akt, phosphatidylinositol 3-kinase/AKT Serine/Threonine Kinase inase p27(Kip) Cyclin-dependent kinase inhibitor; PLK1, Polo like kinase 1; PPAR-γ, Peroxisome proliferator activated receptor gamma; PRC1, Protein Regulator Of Cytokinesis 1; PRKCE, Protein Kinase C Epsilon PKM2 pyruvate kinase M2; PTEN, Phosphatase and tensin homolog; RAF, Rapidly Accelerated Fibrosarcoma; RAS, Rat sarcoma; RHOA, Ras Homolog Family Member A; ROCK2, Rho-associated protein kinase 2; RUNX2, Runt-related transcription factor 2; SERBP1B3, serpin family B member; SERPINE1, Serpin Family E Member 1; SIRT, Sirtuin 1; SLUG, Snail Family Transcriptional Repressor 1(SNAI); SNAI2, Snail Family Transcriptional Repressor 2; SOC1, Son of sevenless homolog 1; SOX1, SRY box transcription factor 1; SP1, Specific protein 1; SPRY1, Sprouty RTK Signaling Antagonist 1; SR-B1, scavenger receptor class B member 1; SREBP2, Sterol Regulatory Element Binding Transcription Factor 2; ST14, transmembrane serine protease matriptase; Sirt7, sirtuin 7; TBX3, T-box transcription factor; TCA, citric acid cycle; TGF-ß, Transforming Growth Factor Beta 1; TGFBR2, transforming growth factor beta receptor 2; TLR, toll like receptor; TNFRS F10c, Tumor necrosis factor receptor superfamily member 10C; TRAF6, Tumor necrosis factor receptor-associated factor 6; TWF1, twinfilin actin binding protein 1; UBC9, ubiquitin carrier protein 9; Wnt, Wingless-related integration site; ZEB2, zinc finger E-box binding homeobox 2; c-MYC, Cellular myelocytomatosis oncogene; miR30c-MAML-YAP/TAZ, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ).

The Role of miRNAs in Age-Related BC

miRNAs can be categorized as oncogenic miRNAs (Onco-miRNAs), inflammatory miRNAs, and senescence-associated miRNAs, as they have been shown to influence the aging process (Sandiford et al., 2018). miRNAs are also important modulators of cell activity and have been linked to cancer and aging (Sun and Liu, 2017). Immunosenescence refers to age-related changes in the T cell compartment that impair immunity. It is also referred to as “inflammatory aging” and is defined by the age-related increase in inflammatory responses, with a systemic proinflammatory state induced by inflammatory aging being associated with cancer. They are influenced by miRNAs such as miR-29, miR-155, and miR-181b (Ma et al., 2011). An age-related decrease in plasma levels of miR-20a-3p, miR-30b-5p, miR106b, miR191, and miR-301a has been demonstrated (Hatse et al., 2014). miRs (−301a and −206), which are known to inhibit luciferase in pMIR-R/Tac1/SG, were also downregulated in BC following experiments on cancer cells (Greco and Rameshwar, 2007). miR-34a has also been elevated to be increased in brain tissue, peripheral blood mononuclear cells, and plasma of aged rats (Li et al., 2011). While miR-34a antisense reduces senescence of aged mesangial cells by upregulating SOD2 (superoxide dismutase 2) and reducing ROS, overexpression of miRNAs-34a leads to premature senescence of young mesangial cells by downregulating SOD2, resulting in increased ROS formation and triggering BC (Bai et al., 2011).

The signaling pathways that are controlled in this matter include the following: NF-kB, IL-6, PTEN, JAK/STAT3, socs1 (suppressor of cytokine signaling 1), PIK3R1 FOXO3a (forkhead box protein O3) c-MYC (cellular myelocytomatosis oncogene)/CREBPβ (CREB-binding protein), Notch signaling, Bcl-2, SirT1, Keap1(Kelch-like ECH-associated protein 1), TLR (Toll-like receptor), NRF2 (nuclear factor erythroid 2-related factor 2), P27/KEAP1/AKT, SMAD2 (mothers against decapentaplegic homolog 2), EZH2 (enhancer of zeste homolog 2), hTERT (human telomerase reverse transcriptase), and BRCA1(BReast CAncer gene 1). Table 2 describes the types of miRNAs involved in the regulation of age-related BC pathways.

Table 2.

Types of MicroRNAs That Are Involved in Regulating Age-Related Breast Cancer Pathways

MicroRNAs(miRNAs)	Mechanisms underlying obesity-related breast cancer (BC)	Target genes and pathways	Details	Reference
miRNA-21	Inflamm-aging, DNA damage (oxidative stress)	TPMI, phosphatase, PTEN, PDCD4 NF-kB, IL-6	The inhibition of MSCs and inflammatory monocyte recruitment is crucial in preventing BC metastasis. Research has shown a connection between reduced levels of miR-126 and lower metastasis-free survival rates in BC patients. The miR-21 gene promoter includes sites where the transcription factor STAT-3 binds when activated by the IL-6 signaling pathway. Elderly individuals were found to have increased levels of proinflammatory cytokines such as IL-6, highlighting the association between aging and tumorigenesis. Moreover, NF-κB promotes the invasion of BC cells by upregulating the expression of oncomiR miR-21 in response to DNA damage.	Cătană et al., 2015; Cosentino et al., 2019
miRNA-126	Inflamm-aging	NF-kB	In the phenotype of senescent cells, the expression of inflammation-suppressing miR-126 was decreased, while the levels of inflammatory proteins were elevated in senescent human aortic endothelial cells.	Cătană et al., 2015
miRNA-146a	Inflamm-aging	STAT3, TRAF6 NF-kB, IL-6	Multiple research studies have demonstrated the importance of the increased expression of NF-kB/miR-146a in BC. Furthermore, miR-146 exhibits anti-inflammatory properties and overall inhibitory effects. miR-146a plays a crucial role in controlling the levels of different inflammatory signaling molecules such as TRAF6.	Cătană et al., 2015
miRNA-146b	Inflamm-aging	STAT3, TRAF6 NF-kB, IL-6	miR-146b levels rise as individuals age and inhibit the production of proinflammatory cytokines IL-6 and IL-8, which are associated with aging. The process includes the involvement of signal transducer and activator of transcription 3 (STAT3), as well as the mediation of interleukin-6 (IL-6). This could be a mechanism through which chronic inflammation contributes to the development of BC, a common oncogenic occurrence. miR-146b is a gene directly targeted by STAT3, with reduced expression in tumor cells and increased expression in normal breast epithelial cells. Furthermore, miR-146b hinders the NF-κB-dependent generation of IL-6, leading to decreased STAT3 activation and suppression of IL-6/STAT3-induced migration and invasion in BC cells. Therefore, a higher miR-146b level was found to be linked to improved patient survival in BC subtypes exhibiting elevated IL6 expression and STAT3 phosphorylation. The application of antagomirs targeting breast tumor cells represents a novel and highly significant therapeutic approach for aging.	Cătană et al., 2015; Gerasymchuk et al., 2020
miRNA-155	Inflamm-aging, telomer shortening, oxidative stress	3′UTR of TRF1 C/EBPβ, SOCS1, JAK, socs1, PIK3R1-FOXO3a-cMYC	One of the numerous miRNAs, specifically known as miR-155, functions as a link connecting inflammation to the development of BC. The increased presence of miR-155 within BC cells results in the ongoing activation of signal transducer and activator of transcription 3 (STAT3) via the Janus-activated kinase (Andersen et al.) pathway. The expression of miR-155 significantly rises in response to inflammatory cytokines such as IFN-γ, interleukin-6 (IL-6), lipopolysaccharide (LPS), and polyriboinosinic: polyribocytidylic acid. Additionally, suppressor of cytokine signaling 1 (socs1) emerges as a new target of miR-155 in BC cells, contributing to the maintenance of STAT3 activation. Modulating miR-155 levels within cells impacts TRF1 levels and the quantity of TRF1 at telomeres. Altered TRF1 expression due to elevated miR-155 levels leads to increased telomere fragility and alterations in the structure of metaphase chromosomes. Glucose deprivation induces oxidative stress in cancer cells. An established aspect of the metabolic reprogramming of BC cells entails the involvement of miRNAs, among which miR-155 plays a crucial role in enhancing the expression of hexokinase II (HKII) to kick-start glycolysis. This specific miRNA impacts different pathways that regulate HKII: initially, by directly diminishing miR-143, an HKII inhibitor, via the suppression of C/EBPβ; second, by liberating STAT3 from its suppressor SOCS1 to enhance HKII function; and third, by favorably influencing HKII expression through the disruption of the PIK3R1-FOXO3a-cMYC axis.	Cătană et al., 2015, Cosentino et al., 2019, Dinami et al., 2014
miRNA-34a	Senescent cell	SirT1, Bcl-2, survivin, CCND1, MDR1, Notch1, GFRA3)Notch signaling targets (Hes1, Hes5)	The excessive presence of miR-34a, a TS-miRNA that inhibits the synthesis of Bcl-2 and SirT1 (proteins with elevated expression levels in breast tumors associated with cellular growth and division), triggers the aging process in cancer cells. This particular miRNA hinders the formation of new blood vessels by promoting cell senescence through SirT. N1-34a-NPs can modulate Notch signaling and the downstream targets of miR-34a in TNBC cells to induce senescence, consequently reducing cell proliferation and movement.	Cătană et al., 2015; Valcourt and Day, 2020
miRNA-34c	Inflamm-aging, senescent cell	NF-kB	Elevated levels of miR-34c have been noted in senescent cells as well as in the bloodstream of women with BC, with decreased miR-34c expression playing a crucial role in advancing to more severe stages of the disease. This miRNA also regulates NF-kB and may be classified as an inflammation-associated miRNA.	Cătană et al., 2015
Let-7	Senescent cell	p53	The Let-7 miRNAs exhibit an increase in expression within senescent cells, thereby impeding the proliferation of tumors and playing a role in the progression of aging.	Cătană et al., 2015
miRNA-195	Inflamm-aging	NF-kB	miR-195, known for its role in triggering NF-kB activation, is significantly elevated in the bloodstream of individuals diagnosed with BC. The suppression of miR-195 expression shows potential as a therapeutic approach for older patients. As such, miR-195 holds promise as an inflammatory biomarker in ARDs.	Cătană et al., 2015
miRNA-200a	Oxidative stress	Keap1	miR-200a targets the mRNA of Keap1, resulting in the initiation of its degradation.	Cătană et al., 2015; Eades et al., 2011
miRNA-335	Cellular senescence, inflamm-aging	TLR and NF-κB	Cellular senescence encompasses a variety of pathways, including the Toll-like receptor (TLR) and NF-κB pathways, which are essential for comprehending the aging process at the cellular level. A noteworthy discovery suggests that the expression of miR-335 is markedly elevated in both naturally senescent cells and cancer cell-induced senescent fibroblasts, shedding light on the potential significance of this miRNA in mechanisms related to senescence. Additionally, research has demonstrated that the increase in miR-335 results in the enhancement of factors linked to the senescence-associated secretory phenotype (SASP), such as interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP1). Noteworthy, SIRT1, a multifaceted transcription factor, emerges as a crucial regulator of SASP and cellular senescence, underscoring its intricate involvement in the aging process at the molecular level.	Gerasymchuk et al., 2020; Tomé et al., 2014
miRNA-19b	Telomere shortening	PTEN	Overexpression of miRNA-19b resulted in a 1.5- to 1.7-fold elevation in telomerase activity within melanoma cells and has been linked with tumorigenesis in BC.	Eckburg et al., 2020
miRNA-222	Senescent cell	p27/kip1 PTEN/Akt Lamin B receptor	LBR knockdown or overexpression of miR-222 led to the stimulation of normal fibroblasts (NFs) to exhibit the characteristics of cancer-associated fibroblasts (CAFs), including heightened migration, invasion, and senescence. Additionally, the medium conditioned by these fibroblasts resulted in increased migration and invasion of BC cells. miR-222 directly targets lamin B receptor (LBR) in breast fibroblasts, and its expression is decreased in breast CAFs compared with matched NFs.	Chatterjee et al., 2019
miRNA-3613-3p	Senescent cell	SMAD2 and EZH2	An in vivo investigation demonstrated that the increased expression of miR-3613-3p suppressed the formation of TNBC tumors and had a notable inhibitory impact on palbociclib in MDA-MB-231 cells. Specifically, it was discovered that SMAD2 and EZH2 were direct targets of miR-3613-3p, influencing the proliferation of TNBC cells and the cells’ response to palbociclib by promoting cellular senescence.	Yu et al., 2020
miRNA-27b	Oxidative stress	Pyruvate dehydrogenase Protein X, PTEN PI3K/Akt	BC advancement can be influenced by the targeting of pyruvate dehydrogenase protein X (PDHX), resulting in a modification of the cell’s metabolic composition. The PI3K/Akt pathway, which is frequently mutated in BCs, significantly affects metabolism and reactive oxygen species (ROS) production by directly controlling mitochondrial bioenergetics and NADPH oxidase (NOX) enzymes. Conversely, oxidative stress triggers the activation of PI3K and inhibits the function of PTEN, which is an inhibitor of PI3K/Akt signaling.	Cosentino et al., 2019
miRNA-296-5p and miRNA-512-5p	Telomere shortening	hTERT	The levels of miR-296-5p and miR-512-5p expression, which both target hTERT, were reduced in BC cells. Reduced expression of miR-296-5p/512-5p and increased hTERT expression have been linked to unfavorable clinical outcomes in patients with basal-type BC. The introduction of miR-296-5p/512-5p into basal BC cells resulted in decreased telomerase activity, diminished telomere maintenance, and the initiation of replicative senescence and apoptosis pathways. Conversely, the epigenetic suppression of miR-296-5p/512-5p contributed to the hTERT-mediated proto-oncogenic effects, specifically in protecting BC cells from apoptosis.	Loh et al., 2019
miRNA-24-3p	DNA damage	BRCA1	Regulators that govern the transition from G2 phase to M phase are also under the influence of alterations in miRNAs induced by aging in extracellular vesicle particles derived from adipocytes. One specific miRNA, miR-24-3p, is known to target the BC susceptibility gene 1 (BRCA1), which plays a crucial role in DNA repair mechanisms and transcriptional regulation in response to DNA damage. Furthermore, BRCA1 is indispensable for maintaining chromosomal stability, thus safeguarding the integrity of the genome against harmful alterations. The phosphorylation of BRCA1 is crucial for the proper functioning of G2/M cell cycle checkpoints in the context of DNA damage response, as it triggers the activation of CHK1 kinase and collaborates with other key regulators such as p53, p21, and p27.	Yoshida and Miki, 2004

3′UTR, 3′ untranslated regions, ARDs, Age related diseases; AKT, Serine/Threonine Kinase; BRCA1, Breast Cancer gene 1; Bcl-2, B cell lymphoma protein 2; C/EBPβ, CCAAT/enhancer binding protein-beta; CHK1, checkpoint kinase 1; EZH2, Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit; FOXO3a, Forkhead box O1 transcription factor-3; GFRA3, GDNF Family Receptor Alpha 3; Hes1, hairy and enhancer of split-1; IFN-γ,Interferon-gamma; IL-6, Interleukin 6; JAK, Janus kinase; Keap1, Kelch like ECH associated protein 1; MDR1, multidrug resistance protein 1; NF-kB, Nuclear factor kappa-light-chain-enhancer of activated B cells; NF-kB, Nuclear factor kappa-light-chain-enhancer of activated B cells; NOX, NADPH Oxidase; Notch, Neurogenic locus notch homolog protein 1; PDCD4, Programmed Cell Death 4; PIK3R1, Phosphoinositide-3-kinase regulatory subunit 1; PTEN, Phosphatase and tensin homolog; SMAD2, Mothers against decapentaplegic homolog 2; SOCS1, suppressor of cytokine signaling 1; STAT3, Signal transducer and activator of transcription 3; SirT1, sirtuin1; TLR, Toll like receptor; TPMI, Tropomyosin 1; TRF1, Telomeric Repeat Binding Factor 1; cMYC, Cellular myelocytomatosis oncogene; hTERT, human telomerase reverse transcriptase; p27/kip1, Cyclin-dependent kinase inhibitor 1B..

The Specific Regulatory Role of miRNAs in Obesity-Related BC

In the context of BC and obesity-associated BC, the diminished expression of Let-7 correlates with enhanced cellular proliferation and diminished differentiation, thereby facilitating the progression of the neoplastic disease (Kasiappan and Rajarajan, 2017). Let-7 modulates cellular differentiation, proliferation, and metabolic processes by targeting oncogenes such as RAS, HMGA2 (high mobility group AT-hook 2), and MYC (Johnson et al., 2007). The diminished expression of Let-7 engenders the activation of signaling pathways such as PI3K/AKT and mTOR (mechanistic target of rapamycin kinase), thereby facilitating tumor proliferation and survival (Heneghan et al., 2010).

miR-21 targets tumor suppressor genes such as PTEN, PDCD4 (programmed cell death protein 4), and RECK (reversion inducing cysteine-rich protein with Kazal motifs), which are crucial for apoptosis, cell cycle regulation, and metastasis. Its overexpression facilitates enhanced cell survival and metastasis, positioning it as a significant factor in BC advancement. miR-21 expression is heightened by obesity-related factors, including leptin, IR, and proinflammatory cytokines such as IL-6 and TNF-α (Hanusek et al., 2022; Kasiappan and Rajarajan, 2017). This upregulation intensifies miR-21’s oncogenic role, fostering tumor growth and apoptosis resistance in obesity contexts (Si et al., 2007).

The miR-30 family, especially miR-30a and miR-30c, plays a significant role in apoptosis and EMT relevant to cancer progression. miR-30a/c inhibits BC cell growth and metastasis by targeting EMT-related transcription factors such as ZEB2. By preventing EMT, miR-30a/c sustains epithelial traits, thereby diminishing the metastatic capability of BC cells (Chen et al., 2019b; di Gennaro et al., 2018; Shi et al., 2019). The expression of miR-30a/c is frequently reduced due to inflammatory and metabolic changes linked to obesity. This reduction promotes EMT, resulting in enhanced BC metastasis in obese patients (Yamamura et al., 2018).

miR-31 exhibits a context-dependent duality in cancer as a tumor suppressor or oncogene. In BC, it inhibits metastasis by targeting RHOA (RAS homolog family member A) (Kasiappan and Rajarajan, 2017).

In obesity-related BC, decreased miR-31 levels are linked to increased metastasis and cancer cell migration. The inflammation and adipokine signaling in obesity further hinder miR-31, exacerbating BC progression. Therapeutic restoration of miR-31 could curtail invasive behavior in BC cells among obese individuals (Kasiappan and Rajarajan, 2017).

Silencing LATS2 (large tumor suppressor kinase 2) enhances cell survival and invasion, whereas its overexpression has the opposite effect. These results indicate that miR-93 facilitates tumor angiogenesis and metastasis by downregulating LATS2. The findings imply that targeting miR-93 could be a viable strategy to inhibit tumor metastasis (Fang et al., 2012). miR-93 promotes adiposity and IR. We elucidated a complex relationship between increased precursor turnover and adipogenesis. miR-93 regulates T-Box Transcription Factor 3, restricting self-renewal in early precursors. In addition, miR-93 suppresses Sirt7, a key factor in promoting in vivo adipogenesis through precursor differentiation and maturation. In women with IR, the levels of miR-93 show a negative correlation with insulin sensitivity (Cioffi et al., 2015).

miR-124 is a tumor suppressor in BC, regulating key oncogenes and signaling pathways involved in cancer cell proliferation, invasion, and metastasis. In obesity, downregulation of miR-124 enhances cancer cell survival and metastasis, leading to poor prognosis. miR-124 targets cyclin-dependent kinase 4, inhibiting BC cell proliferation, and its downregulation in obesity-related BC promotes uncontrolled cell growth and tumor progression (Feng et al., 2015).

miR-143 regulates lipid metabolism, pertinent to obesity. This miRNA suppresses cancer cell proliferation by targeting oncogenes such as Kirsten rat sarcoma viral oncogene homolog) and Bcl-2, enhancing apoptosis in BC cells (Kasiappan and Rajarajan, 2017; Taroeno-Hariadi et al., 2021).

miR-155, which increases in BC, promotes proliferation, metastasis, and telomere length by targeting RHOA, C-X-C chemokine receptor type 4, SRY-box transcription factor 1, p53, and FOXO3 genes (Kaboli et al., 2015). This miRNA inhibits adipocyte differentiation and brown adipocyte-like phenotype by targeting the C/EBPβ (CCAAT enhancer binding protein-beta) and PPAR-γ (peroxisome proliferator activated receptor-gamma) genes in obesity-related BC and a decrease in the expression of this miRNA has been reported in this condition (Chen et al., 2013).

miR-181a by targeting the ataxia–telangiectasia mutation and TNF-α genes in BC and obesity, respectively, inhibits apoptosis and promotes adipocyte differentiation; in both cases the expression of this miRNA is increased. Increased levels of miR-181a enhance tumor aggressiveness (Kaboli et al., 2015; Li et al., 2013).

miR-221 and miR-222 function as Onco-miRNAs in BC by inhibiting cell cycle regulators such as p27Kip1 (cyclin-dependent kinase inhibitor 1B), resulting in heightened proliferation and apoptosis resistance. These miRNAs are upregulated in obesity-associated BC, promoting the proliferation and viability of malignant cells (Kasiappan and Rajarajan, 2017).

miR-302b sustains SOX2 and c-MYC, facilitating cytokine-induced cancer stem cell-like traits in BC cells cocultured with immature adipocytes. Concurrently, miR-302b in BC modulates RUNX2 (RUNX family transcription factor 2), a PI3K/AKT signaling activator (Taroeno-Hariadi et al., 2021).

The expression of miR-326 inversely correlates with ABCC1 (ATP binding cassette subfamily C member 1) in BC. Moreover, overexpression of miR-326 via mimic transfection reduces ABCC1 levels and enhances drug sensitivity in MCF-7/VP MDR cells (Kasiappan and Rajarajan, 2017).miR-335 functions as a metastasis suppressor in BC by targeting genes related to migration and invasion. Its reduced expression in ORBC correlates with heightened metastatic capability. miR-335 acts to directly suppress SOX4, a pivotal transcription factor linked to EMT and metastasis, which is frequently activated in the proinflammatory context of obesity (Kaboli et al., 2015; Tavazoie et al., 2008).

miR-146a and miR-146b modulate inflammation and exhibit tumor-suppressive roles in BC. In obesity-related BC, decreased miR-146a/b expression triggers NF-κB activation and proinflammatory pathways, facilitating tumor advancement (Kaboli et al., 2015). Restoring miR-146a/b expression diminishes cancer cell growth and metastasis by inhibiting TRAF6 and IRAK1 (Taganov et al., 2006).

miR-210 fosters adipogenesis via Wnt signaling inhibition. In BC, it is elevated under hypoxia and targets E-cadherin and HIF1-α (hypoxia-inducible factor 1). miR-125 acts as a tumor suppressor in BC by inhibiting oncogenes such as HER2 and VEGF. Its reduced expression in obesity-associated BC is linked to unfavorable clinical outcomes, as obesity-related inflammatory cytokines such as TNF-α diminish miR-125 levels, promoting tumor proliferation and angiogenesis (Taroeno-Hariadi et al., 2021).

Regarding the miR-125 family, studies have stated that miR-125a-5p inhibits proliferation by targeting histone deacetylase 4/5, HER3, and human antigen R genes, and miR-125b by targeting erythropoietin receptor, ENPEP (glutamyl aminopeptidase), CK-a, and HER2 causes proliferation. It inhibits cell proliferation, invasion, and metastasis. In this condition, the expression of these two miRNAs decreases (Kaboli et al., 2015). miR-125a-3p and miR-125b-3p promote adipogenesis by targeting RhoA and matrix metallopeptidase 11, respectively. In addition, these two miRNAs are increased in clean conditions related to the desired cancer (Kasiappan and Rajarajan, 2017).

Research indicates that miR-15a, diminished in BC, targets Bcl-2 and Early Region 2 Binding Factor (E2F), thereby mitigating metastasis and enhancing apoptosis (Kaboli et al., 2015). In obesity, this miRNA is elevated, targeting delta-like noncanonical Notch ligand 1, which decreases cell quantity while augmenting preadipocyte size (Andersen et al., 2010).

miR-144 facilitates the progression of tumors through the alteration of energy metabolism, leading to the manifestation of brown/beige-like characteristics in fully developed adipocytes. miR-126 modulates insulin receptor substrate 1, subsequently activating the AMPKα/autophagy pathway and stabilizing HIF1-α expression in adipocytes (Wu et al., 2019).

GLUT1 expression is negatively correlated with miRNA 22, which limits glucose absorption in nontumor cells. Increasing proliferation may reduce invasiveness (Chen et al., 2015a). Furthermore, research has shown that epigenetic downregulation of miR-137 in cancer cells leads to increased glutamine uptake and promotes cancer cell survival in an unfavorable environment (Hanusek et al., 2022).

mDA-MB-231 triple-negative cancer cells release extracellular vesicles (EVs) containing miR-105, which modulate cancer-associated fibroblasts (CAFs) to regulate c-Myc. This results in altered CAF metabolism, enhancing glutaminolysis and glycolysis (Yan et al., 2018).

Estrogen modulates DAB adaptor protein 2 expression and enhances miRNA 191 levels. This mechanism promotes the proliferation of ER+ BC cells in vitro (Hanusek et al., 2022).

Estrogenic activation reduces miR-34b levels in MCF-7 cells. Estrogen binding to the ER-p53 complex inhibits transcriptional activity, lowering miR-34 expression. Consequently, decreased miR-34b expression elevates cyclin D1 and Jagged-1, promoting cell proliferation (Liu et al., 2019).

Leptin diminishes miR-27b, which functions as a tumor suppressor miRNA (Taroeno-Hariadi et al., 2021). miR-27b regulates lipid metabolism by inhibiting PPAR-γ through the targeting of FOXO1 and ST14 (ST14 transmembrane serine protease matriptase) (Chen et al., 2019a; Chen et al., 2018; Li et al., 2019; Lin et al., 2009; Wang et al., 2009).

Lipid-enriched mature adipocytes release exosomes that convey miR-34a to macrophages, thereby inhibiting the anti-inflammatory M2 phenotype through the downregulation of Krüppel-like factor 4 (Pan et al., 2019). miR-34a serves as a pivotal mediator in the aggravation of obesity-associated systemic inflammation and metabolic dysregulation (Pan et al., 2019). Conversely, prior investigations have indicated that miR-34a is downregulated in human breast tissue (Yamakuchi et al., 2008). The overexpression of miR-34a in visceral adipose tissue of individuals classified as overweight or obese is correlated with IR and metabolic inflammation (Pan et al., 2019). miR-34a functions as a tumor suppressor miRNA by attenuating the expression of target genes, including Notch1, BCL-2, SIRT1, fra-1 (fos-related antigen 1), components of the Wnt/β-catenin signaling pathway, and MYC (Christoffersen et al., 2010; Rui et al., 2018; Si et al., 2016; Yang et al., 2013).

Overexpression of miR-24-3p reduces p27Kip1 and Bim expression, thereby promoting BC growth and proliferation (Han et al., 2019; Lu et al., 2015). It also suppresses High Density Lipoprotein-Cholesterol (HDL-C) uptake, lipid metabolism, and steroid hormone intake by inhibiting scavenger receptor B-1 (Wang et al., 2018).

Genome-wide analysis identifies miR-3184-5p and miR-181c-3p as significant regulators in adipocyte-associated BC. The upregulation of miR-3184-5p targets FOXP4-NOTCH, promoting the EMT in cocultured mature adipocyte and BC cells. Conversely, downregulation of miR-181c-3p diminishes PPAR-γ inhibition, subsequently enhancing BC cell proliferation (Taroeno-Hariadi et al., 2021).

Upregulated miR-9-5p may play a role in human obesity development. miR-9-5p downregulated Wnt Family Member 3 (Wnt3a)′s 3′ Untranslated Region (UTR), inhibiting Wnt/β-catenin signaling and promoting mesenchymal stem cell (MSC) differentiation into adipocytes (Zhang et al., 2019). Moreover, miR-9-5p was found to enhance the expression of adipogenesis-related genes, including adipsin, PPAR-γ, and C/EBPα in MSCs. Notably, bioinformatic and luciferase assays demonstrated that miR-9-5p negatively regulates the antitumoral gene ADIPOQ (Chung et al., 2017).

Leptin-induced BC cells show decreased expression of miR-181c-3p. miR-3184-5p targets FOXP4 within the NOTCH-induced EMT pathway in cocultured mature adipocyte and BC cells. The downregulation of miR-1881c-3p diminishes the inhibition of PPAR-γ, consequently promoting the proliferation of BC cells (Rajarajan et al., 2019).

An association has been identified between elevated miR-21-5p levels in macrophages and the expression of proinflammatory cytokines (IL-1β and IL-22). This association is linked to migration and invasion via BRG1 downregulation of the Wnt/β-catenin signaling pathway, which contributes to cancer growth and invasiveness (Martínez-Gutierrez et al., 2022).

In obesity-related BC, the activation of miR-1271 suggests a potential antitumor effect of ERα-E2 by inhibiting EMT. The loss of ERα is implicated in BC metastasis, in part, due to its opposing influence on EMT signaling (Hanusek et al., 2022).

The Specific Regulatory Mechanisms of miRNAs in Age-Related BC

Researchers have identified specific miRNAs linked to cancer, inflammation, and aging. Senescent cells exhibit decreased miR-21 and increased tumor suppressor expression (Bonafè and Olivieri, 2015; Olivieri et al., 2013; Rippe et al., 2012). Elevated miR-21 levels are observed in invasive breast tumors. Among miR-21 targets are tumor suppressors tropomyosin 1 and PTEN, as well as proteins linked to suppression and metastasis (LeBlanc and Morin, 2015; Qi et al., 2009). High miR-21 levels in cancer cells inhibit these proteins, whereas its inhibition reduces tumor growth and invasion (Chen et al., 2015b). The miR-21 promoter harbors STAT-3 binding sites, activated by IL-6 signaling. Increased IL-6 production in the elderly evidences the connection between tumorigenesis and aging (Wolfson et al., 2008). DNA damage leads to histone H3 phosphorylation by mitogen- and stress-activated protein kinase-1, facilitating an open chromatin structure for NF-κB/STAT3-mediated miR-21 transactivation. The upregulation of IL-6 by NF-κB triggers STAT3 activation and its recruitment to the miR-21 promoter during genotoxic stress. miR-21 induction may allow cancer cells to evade DNA damage-induced apoptosis and increase BC metastasis by repressing PTEN and PDCD4 expression (Niu et al., 2012). In addition, miR-21 targets Bcl-2 (Rebbeck et al., 2015).

miR-126, an miRNA pair from a single precursor, inhibits BC metastasis by repressing MSCs and inflammatory monocytes (Zhang et al., 2013). In senescent human aortic endothelial cells, levels of inflammation-repressing miR-126 were decreased, while inflammatory proteins were elevated (Cătană et al., 2015).

miR-146a plays an important role in the modulation of the innate immune response (Labbaye and Testa, 2012). Several studies have shown the relevance of the upregulation of NF-kB/miR-146a in BC. In addition, by counteracting the proinflammatory effects of cellular senescence, miR-146 provides anti-inflammatory effects and general suppressive action (Olivieri et al., 2013). miR-146b increases with age and inhibits proinflammatory cytokines IL-6 and IL-8, potentially linking chronic inflammation to BC. The gene for miR-146b, a direct target of STAT3, shows decreased expression in tumor cells but is elevated in normal breast epithelial cells. Furthermore, miR-146b suppresses NF-κB-mediated IL-6 production, thereby inhibiting STAT3 activation and IL-6/STAT3-driven invasion in BC cells. Consequently, elevated levels of miR-146b correlate positively with patient survival in BC subtypes characterized by heightened IL-6 expression and STAT3 phosphorylation (Ohno et al., 2013; Youm et al., 2013).

One prominent mechanism of BC cell metabolic reprogramming via miRNAs is the miR-155-mediated increase in hexokinase II expression, essential for glycolysis initiation. This miRNA influences several pathways that regulate hexokinase II. miR-155 downregulates C/EBPβ, leading to reduced levels of miR-143, a hexokinase II inhibitor, and liberates STAT3 from SOCS1, thereby promoting hexokinase II; additionally, miR-155 enhances hexokinase II by disrupting the PIK3R1-FOXO3a-cMYC pathway (Jiang et al., 2012; Kim et al., 2018; Lei et al., 2016). miR-155 exemplifies the link between inflammation and BC. Overexpression of miR-155 activates STAT3 via the JAK pathway in BC cells, with inflammatory cytokines enhancing miR-155 expression. Furthermore, socs1 is identified as a target of miR-155, promoting persistent STAT3 activation in BC cells (van Schooneveld et al., 2015; Yao et al., 2012). miR-155 inhibits TRF1 (telomeric repeat binding factor 1) translation by targeting its 3′UTR. Upregulation of miR-155 in BC correlates with decreased TRF1 expression and poorer survival in ER-positive cases. Altering miR-155 expression modifies TRF1 levels and its presence at telomeres. Increased miR-155 leads to TRF1 downregulation, resulting in telomere fragility and disrupted metaphase chromosome structure. Conversely, decreased miR-155 enhances telomere function and genomic stability. These findings suggest that elevated miR-155 compromises telomere integrity, contributing to genomic instability and adverse clinical outcomes in ER-positive BC. Our study highlights the clinical significance of miRNA regulation of shelterin, indicating the presence of “telo-miRNAs” affecting cancer and aging (Dinami et al., 2014).

Higher levels of miR-34c are found in senescent cells and BC patients, with its decreased expression crucial for advanced cancer progression. It regulates NF-kB and may function as an inflamma-miRNA. The elevation of miR-34a, a tumor-suppressive miRNA that inhibits Bcl-2 and SirT1, leads to cancer cell senescence. This miRNA hinders angiogenesis by promoting senescence through SirT (Taylor, 2015). Studies have shown that miR-34a can inhibit the Notch1 signaling pathway, which is highly expressed in TNBC, and prevent tumor growth (Cătană et al., 2015).

The let-7 miRNA triggers p53-mediated cell death and blocks the cell cycle. Furthermore, let-7 is widely recognized as a promoter of cellular aging (Guo et al., 2013). Senescent cells also exhibit increased levels of let-7 miR, contributing to this process (Cătană et al., 2015).

miR-195, which activates NF-kB, is significantly elevated in the bloodstream of individuals with BC and in cellular senescence. Silencing miR-195 expression holds potential as a treatment for older patients. Consequently, miR-195 may function as an indicator of inflammation (Cătană et al., 2015).

The expression of antioxidants and detoxifying enzymes is promoted by NRF2, which was originally believed to act as a protective factor against tumorigenesis (Sporn and Liby, 2012). Various events can trigger the pathogenic activation and accumulation of NRF2, with one common alteration involving Keap1 expression or its capacity to bind and degrade NRF2 stably (Taguchi and Yamamoto, 2017). Keap1 mRNA is targeted by miR-200a, leading to its degradation (Eades et al., 2011).

Cellular senescence involves various pathways, such as the TLR1 and NF-κB pathways, that are crucial for understanding the aging process at the cellular level. An important finding indicates that the expression of miR-335 is significantly increased in both naturally senescent cells and cancer cell-induced senescent fibroblasts, highlighting the potential importance of this miRNA in senescence-related mechanisms. Furthermore, studies have shown that the rise in miR-335 leads to the amplification of factors associated with the senescence-associated secretory phenotype (SASP), including IL-6. Notably, SIRT1, a versatile transcription factor, is identified as a key regulator of SASP and cellular senescence, emphasizing its intricate role in the aging process at the molecular level (Tomé et al., 2014).

miR-19b expression indirectly increases hTERT expression by inhibiting a newly discovered hTERT suppressor gene, paired-like homeodomain1 (PITX1) (Eckburg et al., 2020). PITX1 acts as a negative regulator in the RAS signaling pathway and directly binds to the hTERT promoter region, thereby repressing hTERT transcription and telomerase activity, and also inhibiting cellular proliferation (Eckburg et al., 2020). miR-19b attaches to a complementary sequence in the 3′-UTR of PITX1 mRNA, suppressing PITX1 translation and activating hTERT expression (Eckburg et al., 2020). The overexpression of miR-19b resulted in 1.5- to 1.7-fold increases in telomerase activity in melanoma cells and has been linked to oncogenesis in lung cancer, melanoma, BC, and osteosarcoma (Hanusek et al., 2022; Eckburg et al., 2020).

Lamin B receptor (LBR) modulation of miR-222 triggers normal fibroblasts (NFs) to adopt cancer-associated fibroblast traits, such as increased migration and invasion. Conditioned media from these fibroblasts enhance migration and invasion in BC cells. miR-222 directly influences LBR in breast fibroblasts, with reduced expression in breast CAFs relative to NFs. miR-222 is identified as an Onco-miRNA across several cancers, including BC. It operates within cancer cells rather than stromal cells (Chatterjee et al., 2019). In addition, miR-222 upregulation promotes cancer cell growth via p27/kip1 targeting and contributes to chemoresistance through PTEN/Akt modulation (Wang et al., 2016; Zhang et al., 2014).

EZH2 functions as an oncogene in carcinogenesis. High EZH2 expression correlates with enhanced tumor cell proliferation across various cancers, notably BC (Bachmann et al., 2006). SMAD2 is overexpressed in BC and facilitates tumor progression. Inhibitors targeting TGF-β signaling to reduce Smad2 and Smad3 levels may be therapeutic for cancers, including BC (Papageorgis et al., 2010). Elevation of miR-3613-3p significantly hinders the migration and proliferation of TNBC cells in vitro and in vivo by targeting SMAD2 and EZH2. miR-3613-3p downregulates SMAD2 and EZH2 by binding to their 3′UTR (Yu et al., 2020).

miR-27b causes the progression of this cancer in age-related BC, with the mechanisms mentioned and according to the targeted genes in Table 2. The advancement of BC pathology can be profoundly influenced by the strategic targeting of the pyruvate dehydrogenase protein X, which subsequently results in a significant modification and alteration of the cellular metabolic composition and the associated biochemical pathways (Eastlack et al., 2018). The PI3K/AKT signaling pathway, which is frequently subject to mutations in various forms of BCs, exerts a considerable impact on cellular metabolism and the production of ROS through its direct regulatory role over mitochondrial bioenergetics as well as the activity of NADPH oxidase enzymes involved in oxidative stress responses. Conversely, the phenomenon of oxidative stress instigates the activation of the PI3K signaling pathway while simultaneously inhibiting the functional capacity of PTEN, which serves as a critical inhibitor of PI3K/AKT signaling pathways, thereby underscoring the intricate relationship between these molecular mechanisms in the context of BC progression (Koundouros and Poulogiannis, 2018; Leslie et al., 2003; Yuan and Cantley, 2008).

The quantifiable levels of expression for the miRNAs, miR-296-5p and miR-512-5p, both of which have been identified as targets of the hTERT, exhibited a significant reduction in BC cells, suggesting a potential regulatory role in the malignancy’s progression. The observed decreased expression levels of miR-296-5p and miR-512-5p, when juxtaposed with the concomitant increase in hTERT expression, have been correlated with adverse clinical outcomes in patients diagnosed with basal-type BC, thereby highlighting the importance of these molecular interactions in the pathology of this particular subtype. The deliberate introduction of miR-296-5p and miR-512-5p into basal BC cell lines resulted in a marked reduction in telomerase activity, which in turn led to a decrease in telomere maintenance capabilities, ultimately triggering the pathways associated with replicative senescence as well as apoptosis. In stark contrast, the epigenetic silencing of miR-296-5p and miR-512-5p effectively facilitated the proto-oncogenic functions mediated by hTERT, specifically playing a crucial role in safeguarding BC cells from undergoing apoptosis, thereby suggesting a complex interplay between these regulatory molecules and tumorigenesis (Dinami et al., 2017).

Regulatory Function of Common miRNAs in BC Associated with Both Aging and Obesity

According to the studies, it is estimated that miRNAs LET 7, 21, 93, 155, 221, 222, 335, 146a, 146b, 27b, and 34a could be involved in influencing the signaling pathways of both aging and obesity-associated BC. Also, signaling pathways such as PTEN, C/EBPβ, FOXO3, P27, Kip, Akt, TRAF6, PI3K, Bcl2, SIRT1, and Notch are common in both the aging and obesity process associated with BC. According to the studies, some common miRNAs (21, 155, 222, 146b, 27b, 34a) have an effect on the mentioned signaling pathways, which are shown in Figure 1.

FIG. 1.

Common signaling pathways and miRNAs in regulation of obesity- and aging-related BC. Schematic diagram showing miRNAs that regulate cellular signaling mechanisms shared between aging and obesity associated with BC. miRNAs 221/222 with inhibition of PTEN can increase BC. Also, miRNA 21 does the same by inhibiting PTEN and activating RAS/RAF/MAPK. miRNA 34a can inhibit BC by inhibiting SIRT1 and BCL2. miRNA 155 may increase BC by inhibiting P53 and RAS/RAF/MAPK activation and postpone BC by inhibiting C/EBPB. BC, breast cancer; miRNAs, microRNAs; PTEN, phosphatase and tensin homolog deleted on chromosome 10; SIRT1, sirtuin 1.

As summarized in Figure 1, it appears that common miRNAs in aging and obesity-related BC can regulate BC by targeting pathways such as cell survival, proliferation, and cell signaling mechanisms. So, targeting the genes of these pathways can help the regulatory role of miRNAs in reducing BC.

Therapeutic Potential of miRNAs Against BC

miRNA therapies in BC show promise by influencing gene expression related to tumor growth, spread, and drug resistance. A systematic review of 21 studies focused on miRNA-based therapies for TNBC models. According to this study miR-21, miR-34a, and miR-222 are crucial for antitumoral and antimetastatic effects. Notably, miR-21 was the most studied, showing promise in curbing tumor proliferation and metastasis in TNBC murine models (Grimaldi et al., 2021). In addition, Campos et al. identified important extracellular vesicle-associated miRNAs, such as miR-21 and miR-155, that affect chemotherapy response in BC. Their findings suggest miR-21 and miR-155′s roles in fostering chemoresistance, indicating potential as targets for enhancing chemotherapy efficacy (Campos et al., 2021). Bhaumik et al. demonstrated that miR-146b expression inhibits NF-κB activity and diminishes metastatic capability in human BC cell lines (Bhaumik et al., 2008). Another study demonstrated that decreased miR-27b levels can lead to tamoxifen resistance in BC cell lines (MCF7 and T47D), while increased miR-27b expression improved BC cell sensitivity to tamoxifen, indicating an involvement of miR-27b in hormone therapy for BC patients (Zhu et al., 2016).

Investigation into miRNA regulatory networks shows their integration with noncoding RNAs and signaling pathways. Zhang et al. describe the circRNA-miRNA-mRNA axis in BC, demonstrating circRNAs’ role in sequestering miRNAs and influencing target mRNA expression related to cancer. This complex interaction indicates that targeting miRNAs in these networks may provide diverse therapeutic advantages (Zhang et al., 2021b).

miRNA-based therapies for BC encounter considerable obstacles, such as variable prognostic significance (Grimaldi et al., 2020), delivery and stability challenges (Dinami et al., 2023), off-target effects (Kavishahi et al., 2024), and intricate miRNA interactions within the tumor microenvironment. The heterogeneity of BC subtypes, particularly TNBC, complicates the formulation of universally effective miRNA interventions. Overcoming these challenges necessitates further validation of miRNA targets, enhanced delivery systems, and a more profound comprehension of miRNA functions in cancer biology to improve therapeutic effectiveness and safety (To et al., 2022). According to the results obtained from the research, it seems that focusing on common miRNAs that are related to the link between obesity, puberty, and BC can be a good option for continuing research in the future.

Conclusions

The development of BC is significantly influenced by the complex interaction between obesity and aging, which affects biological pathways regulated by miRNAs. Persistent inflammation, IR, and genomic instability play important roles in this context, but there are still gaps in understanding the specific long-term effects on older individuals. Future research should prioritize longitudinal studies that include age-specific assessments and detailed investigations of miRNA functions. While targeting key miRNAs shows promise in therapeutic approaches, it is important to carefully consider the delivery methods and potential negative outcomes.

Footnotes

Authors’ Contributions

N.M.N.M., M.H., and F.P. made substantial contributions to the conception and design. N.M.N.M., M.H., A.B., and F.P. participated in drafting the article or revising it critically for important intellectual content. All authors gave the final approval of the version to be submitted and any revised version.

Disclosure Statement

No competing financial interests exist.

Funding Information

N.M.N.M., M.H., A.B., and F.P. confirm that their research is supported by Zanjan University of Medical Sciences that is primarily involved in education or research.

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