Estrogen receptor-α signaling in post-natal mammary development and breast cancers

Abstract

Abstract17β-estradiol controls post-natal mammary gland development and exerts its effects through Estrogen Receptor ERα, a member of the nuclear receptor family. ERα is also critical for breast cancer progression and remains a central therapeutic target for hormone-dependent breast cancers. In this review, we summarize the current understanding of the complex ERα signaling pathways that involve either classical nuclear “genomic” or membrane “non-genomic” actions and regulate in concert with other hormones the different stages of mammary development. We describe the cellular and molecular features of the luminal cell lineage expressing ERα and provide an overview of the transgenic mouse models impacting ERα signaling, highlighting the pivotal role of ERα in mammary gland morphogenesis and function and its implication in the tumorigenic processes. Finally, we describe the main features of the ERα-positive luminal breast cancers and their modeling in mice.

The Mammary Gland: Basic Structure and Molecular Signaling during Development

“…Estrogen is the critical regulator of branching in the pubertal mammary gland. E2, the female sex steroid hormone, is synthesized and secreted primarily by granulosa cells of developing follicles in the ovary during the estrous and menstrual cycle [ 4 , 153 , 154 ]. E2 is also synthesized locally by adipose tissue in the mammary gland.…”

“…E2 is also synthesized locally by adipose tissue in the mammary gland. E2 signaling is mediated by two receptors, ERα and ERβ, in 30% of mammary luminal epithelium, while basal cells do not express ER-receptors [ 153 , 155 , 156 , 157 ]. Both humans and rodents have ERα and ERβ have a similar sequence homology and binding affinity for E2.…”

“…Studies have demonstrated that loss of ERα signaling causes a deleterious mammary phenotype and impaired function, whereas ERβ loss does not. The multiple regulatory elements regulate the ERα gene (ESR1) expression, including transcription factors, chromatin environment, autocrine, paracrine, and endocrine secreted factors and multiple environmental factors (cell–cell and matrix interactions, mechanical forces) [ 153 ]. The ERα receptor has six structural domains along with two sub-domains, namely, a ligand-independent (AF-1) and a ligand-dependent (AF-2) subdomain.…”

Zinc Signaling in the Mammary Gland: For Better and for Worse

“…Under these conditions, extreme defects in morphology and function, including oxidative stress and inflammation, are described in the non-lactating [ 63 , 64 ] as well as in the lactating gland [ 65 ]. During puberty, growth and differentiation of the epithelial glandular structures within the fat pad are driven by the growth hormones, EGF and IGF-1, as well as by the estrogen receptor [ 66 ]. Interestingly, all of these pathways are modulated by Zn 2+ , as described above [ 67 ].…”

“…Development of the normal breast is mostly regulated by estrogen acting through the ER [ 168 ], thereby controlling a variety of functions, including cell proliferation, angiogenesis, and apoptosis [ 66 ]. The ER signaling is used by breast cancer cells and, in the initial stages of the disease, serves as a major, estrogen-driven, survival pathway [ 168 , 169 , 170 ].…”