Quantitative Studies of Ductal Versus Alveolar Differentiation from Rat Mammary Clonogens

Abstract

In a program aimed at defining and characterizing the cellular origins of radiogenic mammary cancer, we developed and have used a quantitative rat mammary cell transplantation model to investigate hormonal control of differentiation, growth, and response to ionizing radiation. In this model, in response to appropriate hormonal stimulation, a subpopulation of transplanted mammary epithelial cells gives rise to either alveolar colonies (AU) or ductal colonies (DU). The cumulative data support the conclusion that both types of colonies are derived from single clonogenic mammary cells. In the current experiments the glucocorticoid, Cortisol, which does not induce mammary proliferation or differentiation alone, promoted AU formation with milk secretion from grafted clonogens when present with estrogen and/or pituitary MtH (primarily prolactin and growth hormone) from co-grafted MtT. Progesterone synergized with estrogen in a dose-dependent fashion in induction of DU formation in mammary cell grafts in ovariectomized MtT-co-grafted rats and antagonized gluco-corticoid-dependent AU development in such grafts in adrenalectomized-ovariectomized MtT–co-grafted rats as well. We conclude that hormonal regulation of growth and differentiation of rat mammary glands in situ is mediated to a significant extent through effects on the mammary clonogens and their immediate progeny. The mammary clonogen transplantation model permits quantitative investigation of such hormone actions on a mammary clonogen basis in vivo.