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

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.