Katanin P80 expression correlates with lymph node metastasis and worse overall survival in patients with breast cancer

Abstract

OBJECTIVE:

The aim of this study was to investigate the correlation of katanin P80 expression with clinicopathological features and overall survival (OS) in surgical breast cancer (BC) patients.

METHODS:

Four hundred and fourteen BC patients underwent surgery were analyzed in this retrospective cohort study. Katanin P80 expression was examined by immunofluorescence assay. The median follow-up duration was 118.0 months (quantiles: 99.0–140.5 months), the last follow-up date was Jul 1^st 2017.

RESULTS:

Eighty-five patients (20.5%) with katanin P80 positive expression and 329 patients (79.5%) with katanin P80 negative expression were observed in this research. Katanin P80 positive expression was correlated with higher $N$ stage ( $p<$ 0.001) and TNM stage ( $p<$ 0.001). K-M curve and log-rank test revealed that katanin P80 positive patients presented with shorter OS compared with katanin P80 negative patients ( $p<$ 0.001). Multivariate Cox’s regression analysis disclosed that katanin P80 positive expression ( $p<$ 0.001) and histologic grade ( $p<$ 0.001) could independently predict unfavorable OS. Furthermore, subgroups analysis was performed, which illuminated that katanin P80 positive expression was correlated with shorter OS in all subgroups divided by molecular subtyping and TNM stage (all $p<$ 0.05) except in TNM stage I subgroup ( $p=$ 0.573).

CONCLUSION:

Katanin P80 expression positively correlated with lymph node metastasis and could abe a novel biomarker for prognosis in BC patients.

Keywords

Katanin P80 breast cancer lymph node metastasis prognostic factor overall survival

1. Introduction

Breast cancer (BC), one of the most common diagnosed carcinomas among females worldwide, leads to estimated 1676,700 cases and 521,900 deaths happened during 2012, which respectively accounts for 25% of all cancer cases and 15% of cancer deaths among females [1]. In America, the number of females who are diagnosed with BC has increased to 246,660 during 2016, accounting for 29% of all kinds of cancer [2]. In addition, the prognosis of BC patients has been reported to be poor due to high metastases, degree of malignance or therapy resistance [3, 4, 5, 6, 7]. According to the biological characteristics of BC, there are three common diagnostic and prognostic biomarkers, including human epidermal growth factor receptor (HER-2), estrogen receptor (ER) and progesterone receptor (PR) that can guide therapy, while there are still some disadvantages about these three biomarkers, such as unsuitability for some BC patients and bias during the assessment of receptor status [8, 9, 10, 11, 12, 13]. Therefore, more effective and reliable biomarkers should be developed to monitor tumor progression and predict the prognosis of BC patients.

Katanin, a family member of ATPase, is composed of katanin P60 (that is responsible for enzymatic activity) as well as katanin P80 (that is a regulatory subunit encoded by KATNB1 gene), among which p60-microtubule interacting and trafficking (MIT) and p80 C-terminal domain (p80-CTD) have been identified to form a heterodimer, which contribute to the progression of several cellular processes [14, 15, 16, 17, 18]. As one of most common subunit of katanin, katanin P80 is a kind of microtubule-serving protein and plays a role in the formation of a microtubule-based structure (such as manchette and flagellum), thereby affecting meiosis, nuclear shaping, and flagellum formation of sperm [15, 19, 20, 21, 22]. Also, the mutation in katanin P80 has been proved to contribute to left-right asymmetry and heart defects, complex cerebral malformations, male gamete production and human cortical development [15, 23, 24]. According to previous studies, katanin P80 presents with aberrant expression in the pathological processes of spastic paraplegia, Alzheimer’s disease and other cell cycle diseases, while little was known about the role of katanin P80 in carcinomas, especially BC [15, 23]. Therefore, this study aimed to investigate the correlation of katanin P80 expression with clinicopathological features and overall survival (OS) in surgical BC patients.

2. Methods

2.1 Participants

Four hundred and fourteen BC patients underwent surgery in the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, from Jan 2004 to Dec 2008, were analyzed in this retrospective cohort study. Patients with confirmed diagnosis of primary BC by pathological examination, detailed baseline clinicopathological properties before surgery (at least histologic grade, TNM stage, and HER-2, ER, PR expression status), regularly followed up with OS data available, formalin-fixed and paraffin embedded tumor tissue obtained during the surgery and stored in Pathology Department which was available to be detected by immunofluorescence, were reviewed in this study. The study was approved by the Ethical Committee of the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology. And patients or their families provided signed informed consents or oral agreements with tape recording.

2.2 Baseline data retrieval

Baseline data before surgery were retrieved from Hospital Electronic Medical Records System or Medical Records Room including age, gender, histologic grade, T stage, N stage, M stage, according TNM stage and status of ER, PR and HER-2. TNM stage was assessed according to the 6^th edition of the American Joint Committee on Cancer (AJCC) cancer staging criteria. HER-2, ER and PR expression was assessed by immunohistochemistry as routine examination, and immunostaining above 10% was defined as positive expression.

2.3 Follow up and OS calculation

Patients were followed up every 3 months within the first year post surgery, and every 3–12 months in the lasting period according to patients’ willing. The median follow-up duration was 118.0 months (quantiles: 99.0–140.5 months), the last follow-up date was Jul 1^st 2017. OS was calculated from the time of BC surgery to the time of death from any cause.

2.4 Sample and immunofluorescence assay (IF)

Tumor tissue was obtained from the Department of Pathology of our hospital, which stored the samples collected during the surgery. The tumor issue was formalin fixed and paraffin embedded. After embedding and dehydrating at 65 ${}^{\circ}$ C for 3 h, the piece was washed with phosphate buffered saline (PBS) of pH 7.3, primary antibody (Anti-katanin P80 antibody, ab224171, Rabbit polyclonal to Katanin P8, Abcam, USA) was diluted by 1% bovine serum albumin (BSA) and incubated with the slide at 4 ${}^{\circ}$ C overnight. Then, washing with PBS for three times, the slide was added the second antibody (Anti-rabbit IgG (H $+$ L) F (ab’) 2 Fragment (Alexa Fluor ${}^{\@setsize{\scriptsize}{8pt}{\viipt}{\@viipt}\textregistered}$ 488 Conjugate) #4412 (green), CST, USA) and counterstained with Hoechst 33342. We adopted an Olympus BX63 microscope and cellSens Dimension (Version1.8) software (Olympus, Japan) to get images of immunofluorescent staining. In addition, we detected the intensity of katanin P80 staining by the semiquantitative method [25]. The staining strength was defined according to the scoring criteria as follows: 0 (no staining); 100 (weak staining); 200 (modest staining); and 300 (strong staining). Then, we counted 100 cells within each field and calculated the mean number of positive cells to obtain the rate of positive cells by choosing five high-power fields of the most uniformly stained area. Lastly, the result was divided into two groups: negative (final value $\leqslant$ 100, positive (final value $>$ 100) by multiplying the score of staining strength with the percentage of positive cells.

2.5 Statistics

SPSS 22.0 (IBM, USA) and Microsoft Office 2015 (Microsoft, USA) were used for statistical analysis in this study. Data was mainly presented as count (percentage), mean $\pm$ standard deviation (SD) or median (1/4–3/4 quartile). Comparison between two groups was analyzed by $t$ test or Chi-square test. Kaplan-Meier (K-M) curves were drawn for OS analysis, and comparison of OS between two groups was analyzed by log-rank test. Univariate Cox proportional hazard regression was performed to analyze the baseline factors influencing OS, while multivariate Cox proportional hazard regression was performed to analyze baseline factors with a $p$ value below 0.1 in univariate Cox analysis. $p<$ 0.05 was considered as significant.

3. Results

3.1 Study flow

One thousand one hundred seventy five BC patients from 2004 to 2008 were reviewed in this study, of whom 537 patients were excluded (72 cases were secondary BC patients, 465 cases were not received surgery treatment), leading to 638 primary BC patients who received surgery. After that, 135 patients were excluded because that 69 patients lacked data and 66 patients lost following up without OS data, and the remaining 503 patients completed the baseline data and OS data. Then, 89 patients were excluded mainly because formalin-fixed and paraffin embedded tumor tissues were not available to detect by IF. Finally, a total of 414 primary BC patients were included in this study and finished follow up (Fig. 1).

Table 1
Baseline characteristics of BC patients

Parameter	Patients ( $N=$ 414)
Age (years)	53.71 $\pm$ 12.95
Tumor size (cm)	3.0 (2.0–4.0)
Histologic grade	414 (100%)
I (n/%)	88 (21.3)
II (n/%)	305 (73.7)
III (n/%)	21 (5.1)
T stage	414 (100%)
I (n/%)	117 (28.3)
II (n/%)	270 (65.2)
III (n/%)	27 (6.5)
N stage	414 (100%)
0 (n/%)	190 (45.9)
I (n/%)	131 (31.6)
II (n/%)	76 (18.4)
III (n/%)	17 (4.1)
M stage	414 (100%)
0 (n/%)	414 (100.0)
I (n/%)	0 (0.0)
TNM stage	414 (100%)
I (n/%)	45 (10.9)
II (n/%)	270 (65.2)
III (n/%)	99 (23.9)
State of receptor expression N (%)	414 (100%)
HER2 positive (n/%)	135 (32.6)
ER positive (n/%)	272 (65.7)
PR positive (n/%)	235 (56.8)

Data was presented as mean $\pm$ standard deviation, median (25^th–75^th) or count (%). BC, breast cancer; HER2, human epidermal growth factor receptor 2; ER, estrogen receptor; PR, progesterone receptor.

Figure 1.

Study flow.

Figure 2.

Katanin P80 expression in BC patients. Immunofluorescence staining of katanin P80 was indicated that katanin P80 was expressed in cytoplasm: (A) Katanin P80 negative expression; (B) Katanin P80 positive expression. Scale bar, 50 $\mu$ m.

3.2 Baseline characteristics

Mean age of patients was 53.71 $\pm$ 12.95 years. The mean value of tumor size was 3.0 (2.0–4.0) cm. There were 88 (21.3%), 305 (73.7%) and 21 (5.1%) patients with histologic grade I, grade II and grade III respectively. The number of patients in T stage I, stage II and stage III was 117 (28.3%), 270 (65.2%) and 27 (6.5%) respectively. Besides, all patients were diagnosed as M stage 0. According to the molecular subtyping, 135 (32.6%), 272 (65.7%) and 235 (56.8%) patients were ER positive expression, HER2 positive expression and PR positive expression respectively. Other baseline characteristics were shown in Table 1.

Table 2
Univariate Cox analysis of baseline factors predicting OS

	Univariate Cox proportional
	hazard regression
	$P$ value	HR	95% CI
			Lower	Higher
Katanin p80 positive	$<$ 0.001	2.688	1.874	3.857
Age $\geqslant$ 50 years	0.152	0.842	0.665	1.066
Histologic grade	$<$ 0.001	2.217	1.523	3.225
T stage	0.053	1.384	0.996	1.923
N stage	0.001	1.386	1.150	1.670
TNM stage	$<$ 0.001	1.810	1.335	2.455
HER2 positive	0.447	0.860	0.584	1.267
ER positive	$<$ 0.001	0.438	0.309	0.622
PR positive	$<$ 0.001	0.499	0.350	0.712

Univariate Cox proportional hazard regression was performed to analyzed the baseline factors influencing OS. $p<$ 0.05 was considered significant. HER2, human epidermal growth factor receptor 2; ER, estrogen receptor; PR, progesterone receptor. HR, Hazard Ratio.

3.3 Katanin P80 expression in BC patients

Immunofluorescence assay was used to evaluate the katanin P80 expression, and it revealed that katanin P80 mainly expressed in cytoplasm (Fig. 2A and B). There were 85 patients (20.5%) with katanin P80 positive expression and 329 patients (79.5%) with katanin P80 negative expression.

3.4 Correlation of katanin P80 expression with clinicopathological properties

The correlation of katanin P80 expression with clinicopathological properties was analyzed (Fig. 3). Higher N stage (Fig. 3D, $p<$ 0.001) and TNM stage (Fig. 3E, $p<$ 0.001) were presented in katanin P80 positive group than katanin P80 negative group. However, there was no difference between two groups in other clinicopathological properties such as age (Fig. 3A), histologic grade (Fig. 3B), T stage (Fig. 3C), ER status (Fig. 3F) and HER-2 status (Fig. 3H) (All $p>$ 0.05).

Table 3
Multivariate Cox analysis of baseline factors predicting OS

	Multivariate Cox proportional
	hazard regression
	$P$ value	HR	95% CI
			Lower	Higher
Katanin p80 positive	$<$ 0.001	3.173	2.127	4.733
Histologic grade	$<$ 0.001	2.480	1.684	3.653
T stage	0.850	1.041	0.686	1.579
N stage	0.298	0.822	0.569	1.188
TNM stage	0.080	1.801	0.932	3.479
ER positive	0.022	0.549	0.328	0.917
PR positive	0.217	0.721	0.429	1.212

Multivariate Cox proportional hazard regression was performed to analyzed baseline factors with a P value below 0.1 in univariate Cox analysis. $p<$ 0.05 was considered significant. HER2, human epidermal growth factor receptor 2; ER, estrogen receptor; PR, progesterone receptor. HR, Hazard Ratio.

Figure 3.

Correlation of P80 expression with clinicopathological properties. Correlation of P80 expression with clinicopathological properties, including Age (A), B. Histologic grade (B), T stage (C), N stage (D), TNM stage (E), ER status (F), PR status (G), and HER-2 status (H). Katanin P80 positive expression was correlated with higher N stage and TNM stage, which was not different from katanin P80 negative in other clinicopathological properties. Comparison between two groups was analyzed by Chi-square test. $p<$ 0.05 was considered as significant.

3.5 Correlation of katanin P80 expression with OS

K-M curve and log-rank test were performed to evaluate the correlation of katanin P80 expression with OS in BC patients (Fig. 4). It was obvious that patients with katanin P80 positive expression had shorter OS than that in patients with katanin P80 negative expression ( $p<$ 0.001).

3.6 Analysis of factors affecting OS

Analysis of factors influencing OS was assessed by univariate Cox’s analysis (Table 2). Katanin P80 positive expression ( $p<$ 0.001), histologic grade ( $p<$ 0.001), N stage ( $p=$ 0.001) and TNM stage ( $p<$ 0.001) were negatively correlated with OS, while ER positive expression ( $p<$ 0.001) and PR positive expression ( $p<$ 0.001) were correlated with better OS in BC patients. Multivariate Cox analysis was used to further analyze the possible factors that could independently predict OS (Table 3). Katanin P80 positive expression ( $p<$ 0.001) and histologic grade ( $p<$ 0.001) could independently predict shorter OS in BC patients.

3.7 Correlation of katanin P80 expression with OS in subgroups

In Fig. 5, patients with katanin P80 positive expression in subgroups of TNM stage II (Fig. 5B, $p=$ 0.011) and stage III (Fig. 5C, $p=$ 0.001) had worse OS compared to patients with negative expression, while there was no correlation of katanin P80 expression with OS in subgroup of TNM stage I (Fig. 5A, $p=$ 0.573). Meanwhile, katanin P80 positive expression was correlated with shorter OS in other subgroups according to the classification of different molecular subtyping, including ER negative expression (Fig. 5D), ER positive expression (Fig. 5E), PR negative expression (Fig. 5F), PR positive expression (Fig. 5G), HER-2 negative expression (Fig. 5H) and HER-2 positive expression (Fig. 5I) (All $p<$ 0.05).

3.8 Validation in the Cancer Genome Atlas (TCGA) database

In order to further verify the role of katanin P80 in BC, we further validated the results in TCGA database that is a collaboration between the national cancer institute (NCI) and the national human genome research institute (NHGRI) that has generated comprehensive, multi-dimensional maps of the key genomic changes in 33 types of cancer. Cox analysis revealed that high expression of katanin P80 (KATNB1) was numerically correlated with worse OS in BC patients, but without statistical significance ( $p=$ 0.097) (HR: 2.478, 95% CI: 0.850–7.228). In addition, Kaplan-Meier Plot showed no correlation of katanin P80 with OS in BC patients ( $P=$ 0.262) (Fig. 6).

4. Discussion

In this study, we found that (1) katanin P80 positive expression was correlated with higher N stage and TNM stage; (2) K-M curves revealed that katanin P80 positive expression correlated with shorter OS than katanin P80 negative expression, and multivariate Cox analysis disclosed that katanin P80 positive expression could predict OS in BC patients independently; (3) katanin P80 positive expression was correlated with shorter OS in BC patients in all subgroups divided by molecular subtyping and TNM stage except in TNM stage I subgroup.

Katanin P80, a subunit of katanin, plays an important role in microtubule-severing and cytokinesis [26]. An interesting study revealed that the upregulation of katanin P80 could lead to the disorder of microtubule, then affect the abnormal formation and migration in nerve cells [19]. Another study revealed that katanin P80 influences the microtubule-based structures, which widely exits in cellular activities such as mitosis and meiosis, morphogenesis and migration [20, 27]. In addition, BC has been reported that its initiation and metastasis correlate with microtubule actin cross-linking factor 1 (MACF1), which indicates that factors acting on microtubule such as katanin P80 might be related to the metastasis of BC [28, 29, 30, 31]. According to these researches, it is suggested that katanin P80 plays a vital role in regulating the microtubule serving during the meiosis and mitosis and promoting the morphogenesis and migration of tumor cells. A network diagram of Katanin P80 was shown in Supplementary Fig. 1.

Figure 4.

Correlation of P80 expression with OS. K-M curves revealed that katanin P80 positive expression correlated with shorter OS than katanin P80 negative expression. K-M curves were drawn for OS analysis, and comparison of OS between two groups was analyzed by log-rank test. $p<$ 0.05 was considered as significant.

Figure 5.

Correlation of P80 expression with OS in subgroups. Correlation of P80 expression with OS in subgroups of TNM stage I (A), TNM stage II (B), TNM stage III (C), ER negative expression (D), ER positive expression (E), PR negative expression (F), PR positive expression (G), HER-2 negative expression (H), HER-2 positive expression (I). Katanin P80 positive expression was correlated with shorter OS in BC patients in all subgroups divided by molecular subtyping and TNM stage except in TNM stage I subgroup. K-M curves were drawn for OS analysis, and comparison of OS between two groups was analyzed by log-rank test. $p<$ 0.05 was considered as significant.

Although few study has been performed to investigate the role of P80 in carcinomas, there is still one previous study, which suggests that katanin P80 involves in the processes of cytokinesis via the interaction with LAPSER1 gene, while the disorder of this interaction leads to genetic instability in prostate cancer, suggesting that dysregulation of katanin P80 is related to tumor progression [32]. The role of katanin P80 in prostate cancer has been confirmed, while its effects in BC are still unclear. Hence, our study enrolled 414 BC patients and explored the correlation of katanin P80 with clinicopathological characteristics and OS in BC patients, which indicated that katanin P80 positive expression was associated with higher N stage and higher TNM stage. The possible reasons were as followed: (1) the aberrant katanin P80 expression can be helpful for microtubule-serving disorder in BC patients, which would promote migration and metastasis of cancer cell. (2) The dysregulated expression of katanin P80 related to metastasis, which often occurred in higher clinical stages [19, 20, 32, 33, 34, 35].

Figure 6.

Kaplan-Meier Plot for Katanin P80.

As the aspect for prognostic effects of katanin P80 in BC patients, there was few study about the relationship between katanin P80 and OS of BC patients. Thus, our study analyzed the value of katanin P80 in predicting OS in BC patients, which confirmed that katanin P80 positive was correlated with worse OS compared with katanin P80 negative expression, and it could predict OS independently. The feasible reason was that the up-expression of katanin P80 promotes the microtubule-severing effect, inducing the mitosis and migration of BC cells, thereby resulting in shorter OS in BC patients [36, 37, 38].

In the analysis of OS in subgroups, the result of this study was that BC patients with katanin P80 positive expression had worse OS compared to patients with katanin P80 negative expression in all subgroups except TNM stage I subgroup. The reasons were as followed 1) katanin P80 could affect cells migration and cells proliferation by targeting several genes or pathways, including MACF1 or LAPSER1 gene, thereby promoting lymph node metastases in BC patients, suggesting that katanin P80 positively correlates with severe degree of BC. Therefore, the effect of katanin P80 was not obvious in subgroup of TNM stage I. 2) The sample size of TNM stage I was not enough ( $N=$ 45), thus, the role of katanin P80 in BC patients with TNM stage I was still unclear.

There were some limitations of this study: (1) This was a single-center retrospective cohort study, which probably lead to some biases such as recall bias and selection bias. Thus, further study enrolled more patients from multiple centers is greatly needed. (2) This research only enrolled BC patients who received surgeries, while the role of katanin P80 in inoperable patients was not analyzed.

In conclusion, katanin P80 expression positively correlated with lymph node metastasis and could be a novel biomarker for prognosis in BC patients.

Footnotes

Conflict of interest

The authors have no financial conflicts of interest.

Supplementary data

Supplemental Fig. 1.

A network diagram of Katanin P80.

References

Torre

L.A.

Bray

Siegel

R.L.

Ferlay

Lortet-Tieulent

and Jemal

, Global cancer statistics, 2012, CA Cancer J Clin 65 (2015), 87–108.

Siegel

R.L.

Miller

K.D.

and Jemal

, Cancer statistics, 2016, CA Cancer J Clin 66 (2016), 7–30.

Melzer

von der Ohe

and Hass

, Breast carcinoma: From initial tumor cell detachment to settlement at secondary sites, Biomed Res Int 2017 (2017), 8534371.

Pascual

Apellaniz-Ruiz

Pernaut

Cueto-Felgueroso

Villalba

Alvarez

Manso

Inglada-Perez

Robledo

Rodriguez-Antona

and Ciruelos

, Polymorphisms associated with everolimus pharmacokinetics, toxicity and survival in metastatic breast cancer, PLoS One 12 (2017), e0180192.

Choi

J.S.

Kim

K.H.

Shin

Y.K.

Seo

Kim

S.H.

Park

and Choi

Y.L.

, Girdin protein expression is associated with poor prognosis in patients with invasive breast cancer, Pathology 49 (2017), 618–626.

Gonda

Shibata

Ohtake

Matsumoto

Tachibana

Abe

Ohto

Sakurai

and Takenoshita

, Myeloid-derived suppressor cells are increased and correlated with type 2 immune responses, malnutrition, inflammation, and poor prognosis in patients with breast cancer, Oncol Lett 14 (2017), 1766–1774.

Heilmann

Toth

Bossmann

Klimo

Plass

and Gerhauser

, Genome-wide screen for differentially methylated long noncoding RNAs identifies Esrp2 and lncRNA Esrp2-as regulated by enhancer DNA methylation with prognostic relevance for human breast cancer, Oncogene 36 (2017), 6446–6461.

Henry

K.E.

Ulaner

G.A.

and Lewis

J.S.

, Human epidermal growth factor receptor 2-targeted PET/single- photon emission computed tomography imaging of breast cancer: Noninvasive measurement of a biomarker integral to tumor treatment and prognosis, PET Clin 12 (2017), 269–288.

Andreopoulou

Kelly

C.M.

and McDaid

H.M.

, Therapeutic advances and new directions for triple-negative breast cancer, Breast Care (Basel) 12 (2017), 21–28.

10.

Yin

Cheryan

V.T.

Rishi

A.K.

and Reddy

K.B.

, Myc mediates cancer stem-like cells and EMT changes in triple negative breast cancers cells, PLoS One 12 (2017), e0183578.

11.

Locatelli

M.A.

Curigliano

and Eniu

, Extended adjuvant chemotherapy in triple-negative breast cancer, Breast Care (Basel) 12 (2017), 152–158.

12.

Gandara-Cortes

Vazquez-Boquete

Fernandez-Rodriguez

Viano

Insua

Seoane-Seoane

Gude

Gallego

Fraga

Antunez

J.R.

Curiel

Perez-Lopez

and Garcia-Caballero

, Breast cancer subtype discrimination using standardized 4-IHC and digital image analysis, Virchows Arch 472 (2018), 195–203.

13.

Tang

Wang

Zhao

Yang

and Li

, Lymph node status have a prognostic impact in breast cancer patients with distant metastasis, PLoS One 12 (2017), e0182953.

14.

Zehr

Szyk

Piszczek

Szczesna

Zuo

and Roll-Mecak

, Katanin spiral and ring structures shed light on power stroke for microtubule severing, Nat Struct Mol Biol 24 (2017), 717–725.

15.

Selcuk

Kirimtay

Canbaz

Cesur

G.I.

Korulu

and Karabay

, Katanin-p80 gene promoter characterization and regulation via Elk1, PLoS One 8 (2013), e69423.

16.

Takac

Samajova

Pechan

Luptovciak

and Samaj

, Feedback microtubule control and microtubule-actin cross-talk in arabidopsis revealed by integrative proteomic and cell biology analysis of KATANIN 1 mutants, Mol Cell Proteomics 16 (2017), 1591–1609.

17.

Deinum

E.E.

Tindemans

S.H.

Lindeboom

J.J.

and Mulder

B.M.

, How selective severing by katanin promotes order in the plant cortical microtubule array, Proc Natl Acad Sci USA 114 (2017), 6942–6947.

18.

Rezabkova

Jiang

Capitani

Prota

A.E.

Akhmanova

Steinmetz

M.O.

and Kammerer

R.A.

, Structural basis of katanin p60:p80 complex formation, Sci Rep 7 (2017), 14893.

19.

Jin

Pomp

Shinoda

Toba

Torisawa

Furuta

Oiwa

Yasunaga

Kitagawa

Matsumura

Miyata

Tan

T.T.

Reversade

and Hirotsune

, Katanin p80, NuMA and cytoplasmic dynein cooperate to control microtubule dynamics, Sci Rep 7 (2017), 39902.

20.

Pleuger

Fietz

Hartmann

Weidner

Kliesch

O’Bryan

M.K.

Dorresteijn

and Bergmann

, Expression of katanin p80 in human spermatogenesis, Fertil Steril 106 (2016), 1683–1690e1.

21.

O’Donnell

Rhodes

Smith

S.J.

Merriner

D.J.

Clark

B.J.

Borg

Whittle

O’Connor

A.E.

Smith

L.B.

McNally

F.J.

de Kretser

D.M.

Goodnow

C.C.

Ormandy

C.J.

Jamsai

and O’Bryan

M.K.

, An essential role for katanin p80 and microtubule severing in male gamete production, PLoS Genet 8 (2012), e1002698.

22.

W.F.

Pomp

Ben-Omran

Kodani

Henke

Mochida

G.H.

T.W.

Woodworth

M.B.

Bonnard

Raj

G.S.

Tan

T.T.

Hamamy

Masri

Shboul

Al Saffar

Partlow

J.N.

Al-Dosari

Alazami

Alowain

Alkuraya

F.S.

Reiter

J.F.

Harris

M.P.

Reversade

and Walsh

C.A.

, Katanin p80 regulates human cortical development by limiting centriole and cilia number, Neuron 84 (2014), 1240–57.

23.

Furtado

M.B.

Merriner

D.J.

Berger

Rhodes

Jamsai

and O’Bryan

M.K.

, Mutations in the Katnb1 gene cause left-right asymmetry and heart defects, Dev Dyn 246 (2017), 1027–1035.

24.

Mishra-Gorur

Caglayan

A.O.

Schaffer

A.E.

Chabu

Henegariu

Vonhoff

Akgumus

G.T.

Nishimura

Han

Baran

Gumus

Dilber

Zaki

M.S.

Hossni

H.A.A.

Riviere

J.B.

Kayserili

Spencer

E.G.

Rosti

R.O.

Schroth

Per

Caglar

Dolen

Baranoski

J.F.

Kumandas

Minja

F.J.

Erson-Omay

E.Z.

Mane

S.M.

Lifton

R.P.

Keshishian

Dobyns

W.B.

Chi

N.C.

Sestan

Louvi

Bilguvar

Yasuno

Gleeson

J.G.

and Gunel

, Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors, Neuron 85 (2015), 228.

25.

Pavelic

Z.P.

Pavelic

Carter

C.P.

and Pavelic

, Heterogeneity of c-myc expression in histologically similar infiltrating ductal carcinomas of the breast, J Cancer Res Clin Oncol 118 (1992), 16–22.

26.

Benz

Clucas

Mottram

J.C.

and Hammarton

T.C.

, Cytokinesis in bloodstream stage Trypanosoma brucei requires a family of katanins and spastin, PLoS One 7 (2012), e30367.

27.

Sharp

D.J.

and Ross

J.L.

, Microtubule-severing enzymes at the cutting edge, J Cell Sci 125 (2012), 2561–9.

28.

Miao

Ali

Zhao

Yin

Chen

Yang

and Qian

, Microtubule actin cross-linking factor 1, a novel potential target in cancer, Cancer Sci 108 (2017), 1953–1958.

29.

Aseyev

Ribeiro

J.M.

and Cardoso

, Review on the clinical use of eribulin mesylate for the treatment of breast cancer, Expert Opin Pharmacother 17 (2016), 589–600.

30.

Orditura

Gravina

Riccardi

Diana

Mocerino

Leopaldi

Fabozzi

Giordano

Nettuno

Incoronato

Barzelloni

M.L.

Caputo

Pisano

Grimaldi

Genua

Montesarchio

Barbato

Iodice

Lieto

Procaccini

Mabilia

Febbraro

Laurentiis

and Ciardiello

, Eribulin for metastatic breast cancer (MBC) treatment: A retrospective, multicenter study based in Campania, south Italy (Eri-001 trial), ESMO Open 2 (2017), e000176.

31.

Tanaka

Ueno

Nakashima

Chinen

Sato

Masaki

Mogi

Sasaki

Tamura

and Takamatsu

, Retrospective analysis of the efficacy and safety of eribulin therapy for metastatic breast cancer in daily practice, Thorac Cancer 8 (2017), 523–529.

32.

Sudo

and Maru

, LAPSER1 is a putative cytokinetic tumor suppressor that shows the same centrosome and midbody subcellular localization pattern as p80 katanin, FASEB J 21 (2007), 2086–100.

33.

Sachdev

J.C.

and Jahanzeb

, Use of cytotoxic chemotherapy in metastatic breast cancer: Putting taxanes in perspective, Clin Breast Cancer 16 (2016), 73–81.

34.

Arpel

Gamper

Spenle

Fernandez

Jacob

Baumlin

Laquerriere

Orend

Cremel

and Bagnard

, Inhibition of primary breast tumor growth and metastasis using a neuropilin-1 transmembrane domain interfering peptide, Oncotarget 7 (2016), 54723–54732.

35.

Visconti

and Grieco

, Fighting tubulin-targeting anticancer drug toxicity and resistance, Endocr Relat Cancer 24 (2017), T107–T117.

36.

Xiao

Yang

Tang

Cao

and Wang

, Clinicopathological characteristics and prognosis of metaplastic carcinoma of the breast, Oncol Lett 14 (2017), 1971–1978.

37.

Banys-Paluchowski

Witzel

Riethdorf

Rack

Janni

Fasching

P.A.

Solomayer

E.F.

Aktas

Kasimir-Bauer

Pantel

Fehm

and Muller

, Clinical relevance of serum HER2 and circulating tumor cell detection in metastatic breast cancer patients, Anticancer Res 37 (2017), 3117–3128.

38.

Dickler

M.N.

Tolaney

S.M.

Rugo

H.S.

Cortes

Dieras

Patt

Wildiers

Hudis

C.A.

O’Shaughnessy

Zamora

Yardley

D.A.

Frenzel

Koustenis

and Baselga

, MONARCH 1, A phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2- metastatic breast cancer, Clin Cancer Res 23 (2017), 5218–5224.

Katanin P80 expression correlates with lymph node metastasis and worse overall survival in patients with breast cancer

Abstract

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Introduction

2. Methods

2.1 Participants

2.2 Baseline data retrieval

2.3 Follow up and OS calculation

2.4 Sample and immunofluorescence assay (IF)

2.5 Statistics

3. Results

3.1 Study flow

Table 1 Baseline characteristics of BC patients

Table 2 Univariate Cox analysis of baseline factors predicting OS

3.4 Correlation of katanin P80 expression with clinicopathological properties

Table 3 Multivariate Cox analysis of baseline factors predicting OS

3.6 Analysis of factors affecting OS

3.7 Correlation of katanin P80 expression with OS in subgroups

3.8 Validation in the Cancer Genome Atlas (TCGA) database

4. Discussion

Footnotes

Conflict of interest

Supplementary data

References

Table 1
Baseline characteristics of BC patients

Table 2
Univariate Cox analysis of baseline factors predicting OS

Table 3
Multivariate Cox analysis of baseline factors predicting OS