Amphiregulin mediates progesterone-induced mammary ductal development during puberty

Abstract

IntroductionPuberty is a period of increased susceptibility to factors that cause increased breast cancer risk in adulthood. Mammary end buds (EBs) that develop during puberty are believed to be the targets of breast cancer initiation. Whereas the role of estrogen (E) has been extensively studied in pubertal mammary gland development, the role of progesterone (P) during puberty is less defined.MethodsPubertal and prepubertal ovariectomized mice were treated with vehicle control (C), E, P, or E+P. Mammary glands from these mice were analyzed for changes in morphology, proliferation, and expression of the downstream targets amphiregulin (AREG) and receptor activator of NF-κB ligand (RANKL).ResultsP, acting specifically through the progesterone receptor, induced increases in mammary gland proliferation and EB formation that were associated with increased AREG expression in ducts and EBs. E, acting specifically through the estrogen receptor, produced similar responses also mediated by AREG. Blocking AREG action by treatment with an EGFR inhibitor completely abrogated the effect of P on EB formation and proliferation and significantly reduced proliferation within ducts. P also increased expression of RANKL, primarily in ducts. Treatment with RANK-Fc, an inhibitor of RANKL, reduced P-dependent proliferation in ducts and to a lesser extent in EB, but did not cause EB regression.ConclusionsThese results demonstrate a novel P-specific effect through AREG to cause EB formation and proliferation in the developing mammary gland both before and during puberty. Thus, hormones and/or factors in addition to E that upregulate AREG can promote mammary gland development and have the potential to affect breast cancer risk associated with pubertal mammary gland development.

Multiple Molecular Subtypes of Triple-Negative Breast Cancer Critically Rely on Androgen Receptor and Respond to Enzalutamide In Vivo

“…AREG is required for mammary ductal morphogenesis and is the predominant EGF receptor (EGFR) ligand during mammary gland development (27). To date, AR is not known to regulate AREG in breast cancer or normal breast tissue.…”

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

“…HS-MECs are responsible for communicating the endocrine reproductive cues derived from oestrogen and progesterone levels, and converting them into paracrine and autocrine factors able to orchestrate functional differentiation of the mammary epithelium. Therefore, HS-MECs can also be defined by the expression of paracrine factors associated with the growth and differentiation of basal MECs (e.g., WNT4 [1]), or alveolar luminal MECs (e.g., AREG, RANKL [2,3]) in response to ERα and PGR binding their cognate ligands.…”

Bringing androgens up a NOTCH in breast cancer

“…These two sex steroid receptors are also required for side branching of the ductal network, expansion of lobular tissue and terminal differentiation of alveolar MECs to generate milk-producing lobular units during pregnancy (Lydon et al 1995, Hewitt et al 2002, Feng et al 2007, LaMarca & Rosen 2008, Aupperlee et al 2013, Lain et al 2013, Quaynor et al 2013, Sampayo et al 2013. In the absence of pregnancy in rodents and humans, a small degree of glandular expansion and differentiation occurs with every menstrual cycle (Robinson et al 1995).…”