Mammary Gland Development in Adult Mice Requires Epithelial and Stromal Estrogen Receptor α

TLDR

Mammary gland development after puberty depends on estrogen receptor α and progesterone receptor, with stromal ERα essential in immature mice while epithelial ERα is not. The study examines whether the neonatal ERα requirements also apply to adult mammary development. Adult ERα‑deficient or wild‑type epithelial cells were transplanted into epithelial‑free fat pads of 3‑week‑old αERKO or wild‑type recipients. In adult mice, complete mammary development requires both stromal and epithelial ERα, yet high estradiol and progesterone can drive full growth with stromal ERα alone, and ERα‑deficient epithelial cells can still form rudimentary ducts in ERα‑negative stroma, revealing distinct ERα roles in neonatal versus adult tissues and confirming cooperation with epithelial PR.

Abstract

Complete mammary gland development takes place following puberty and depends on the estrogen receptor (ER)α and the progesterone receptor (PR) and is tightly regulated by the interaction of the mammary epithelium with the stromal compartment. Studies using mammary tissues of immature mice have indicated that stromal but not epithelial ERα is required for mammary gland growth. This study investigates whether these same tissue growth requirements of neonate tissue are necessary for mammary development and response in adult mice. Mammary epithelial cells were isolated from adult mice with a targeted disruption of the ERα gene (αERKO) or from wild-type counterparts and injected into epithelial-free mammary fat pads of 3-wk-old female αERKO or wild-type mice. Ten weeks after cell injection, analysis of mammary gland whole mounts showed that both stromal and epithelial ERα were required for complete mammary gland development in adult mice. However, when the mice were treated with high doses of estradiol (E2) and progesterone, stromal ERα was sufficient to generate full mammary gland growth. Surprisingly, ERα-deficient epithelial cells were able to proliferate and develop into a rudimentary mammary ductal structure in an ERα-negative stroma, indicating that neither stromal nor epithelial ERα are required for the mammary rudiment to form in the adult mouse, as confirmed by the phenotype of the αERKO mammary gland. Use of thisin vivo model system has demonstrated that neonatal and adult mammary tissues use a different tissue-specific role for ERα in mammary response. Immunostaining for ERα and PR in the mammary outgrowths supported the view that both stromal and epithelial ERα, in cooperation with epithelial PR, govern mammary gland development in adult mice.