Hormone-Sensing Mammary Epithelial Progenitors: Emerging Identity and Hormonal Regulation

Abstract

The hormone-sensing mammary epithelial cell (HS-MEC-expressing oestrogen receptor-alpha (ERα) and progesterone receptor (PGR)) is often represented as being terminally differentiated and lacking significant progenitor activity after puberty. Therefore while able to profoundly influence the proliferation and function of other MEC populations, HS-MECs are purported not to respond to sex hormone signals by engaging in significant cell proliferation during adulthood. This is a convenient and practical simplification that overshadows the sublime, and potentially critical, phenotypic plasticity found within the adult HS-MEC population. This concept is exemplified by the large proportion (~80 %) of human breast cancers expressing PGR and/or ERα, demonstrating that HS-MECs clearly proliferate in the context of breast cancer. Understanding how HS-MEC proliferation and differentiation is driven could be key to unraveling the mechanisms behind uncontrolled HS-MEC proliferation associated with ERα- and/or PGR-positive breast cancers. Herein we review evidence for the existence of a HS-MEC progenitor and the emerging plasticity of the HS-MEC population in general. This is followed by an analysis of hormones other than oestrogen and progesterone that are able to influence HS-MEC proliferation and differentiation: androgens, prolactin and transforming growth factor-beta1.

Pathobiology of the 129:Stat1 −/− mouse model of human age-related ER-positive breast cancer with an immune infiltrate-excluded phenotype

“…FoxA1 is expressed in ductal progenitor cells [ 63 , 64 ]. The location and distribution of the morphologically unique FoxA1 + LOP cells identified in the present study are consistent with the notion that LOP cells represent a neoplastic form of suprabasal ductal HS-MEC progenitors [ 56 ]. The presence of FoxA1 + /ER + /PR + LOP cells in the 129: Stat1 −/− mammary ducts and neoplasms is also consistent with a ductal, rather than alveolar, origin of the tumors (Figs.…”

“…Recent evidence indicates that FoxA1, a “pioneer transcription factor” [ 51 – 53 ], is necessary for ER expression [ 53 – 55 ] and for branching morphogenesis in the mammary glands by maintaining ductal and alveolar luminal cell lineages from basal stem/progenitor cells [ 54 ]. ER + , PR + , and FoxA1 + MECs belong to a class of “hormone-sensing” (HS) MECs thought to be directly involved in mammary differentiation and in some human breast cancers [ 56 ]. These cells stand out in H&E-stained mammary ducts as morphologically unique, pale, basaloid or suprabasal cells (Additional file 2 : Figure S5).…”

Prolactin Alters the Mammary Epithelial Hierarchy, Increasing Progenitors and Facilitating Ovarian Steroid Action

“…PRL and estrogen cooperate in physiologic states such as early pregnancy (reviewed in Tarulli et al., 2015 ), and estrogen and PRL synergistically regulate some target genes in breast cancer cells ( Fiorillo et al., 2013 , Rasmussen et al., 2010 , Sato et al., 2013 ). In light of PRL's insignificant effect on ERα expression but collaboration with ER-mediated signals to increase PR, we examined transcripts of key co-factors of ERα activity in isolated MECs by qRT-PCR.…”

“…Although considerable research has illuminated the actions of estrogen and progesterone on the mammary gland and the pathways by which these steroids may influence the development of breast cancer (reviewed in Arendt and Kuperwasser, 2015 , Joshi et al., 2012 , Tanos et al., 2012 , Tarulli et al., 2015 , Visvader and Stingl, 2014 ), PRL has remained a hidden partner in these processes. PRL activity is generally associated with pregnancy and lactation, but many factors increase pituitary PRL secretion apart from these physiologic states ( Ben Jonathan et al., 2008 ).…”

“…A rich literature has elucidated the actions of estrogen and progesterone on mammary development and gene expression (reviewed in Arendt and Kuperwasser, 2015 , Joshi et al., 2012 , Stingl, 2011 , Tanos et al., 2012 , Tarulli et al., 2015 ). Identification of surface markers for human and mouse mammary epithelial cell (MEC) subsets and comparison of the transcriptomes between these species have validated the utility of mouse models to investigate hormone actions in MEC differentiation ( Lim et al., 2010 , Shehata et al., 2012 , Tornillo and Smalley, 2015 , Visvader and Stingl, 2014 ).…”