Mueller Stefan O, Clark James A, Myers Page H, Korach Kenneth S
Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Endocrinology. 2002 Jun;143(6):2357-65. doi: 10.1210/endo.143.6.8836.
Complete mammary gland development takes place following puberty and depends on the estrogen receptor (ER)alpha 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 ER alpha 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 ER alpha gene (alpha ERKO) or from wild-type counterparts and injected into epithelial-free mammary fat pads of 3-wk-old female alpha ERKO or wild-type mice. Ten weeks after cell injection, analysis of mammary gland whole mounts showed that both stromal and epithelial ER alpha 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 ER alpha was sufficient to generate full mammary gland growth. Surprisingly, ER alpha-deficient epithelial cells were able to proliferate and develop into a rudimentary mammary ductal structure in an ER alpha-negative stroma, indicating that neither stromal nor epithelial ER alpha are required for the mammary rudiment to form in the adult mouse, as confirmed by the phenotype of the alpha ERKO mammary gland. Use of this in vivo model system has demonstrated that neonatal and adult mammary tissues use a different tissue-specific role for ER alpha in mammary response. Immunostaining for ER alpha and PR in the mammary outgrowths supported the view that both stromal and epithelial ER alpha, in cooperation with epithelial PR, govern mammary gland development in adult mice.
完整的乳腺发育在青春期后发生，依赖于雌激素受体（ER）α和孕激素受体（PR），并受到乳腺上皮与基质成分相互作用的严格调控。使用未成熟小鼠乳腺组织的研究表明，乳腺生长需要基质而非上皮的ERα。本研究调查了新生组织的这些相同的组织生长需求对于成年小鼠乳腺发育和反应是否必要。从雌激素受体α基因靶向敲除（αERKO）的成年小鼠或野生型对照小鼠中分离乳腺上皮细胞，并将其注射到3周龄雌性αERKO或野生型小鼠无上皮的乳腺脂肪垫中。细胞注射10周后，对乳腺整体标本的分析表明，基质和上皮的ERα对于成年小鼠完整的乳腺发育都是必需的。然而，当用高剂量的雌二醇（E2）和孕酮处理小鼠时，基质ERα足以促进乳腺完全生长。令人惊讶的是，ERα缺陷的上皮细胞能够在ERα阴性的基质中增殖并发育成基本的乳腺导管结构，这表明成年小鼠乳腺原基的形成既不需要基质ERα也不需要上皮ERα，αERKO乳腺的表型证实了这一点。使用这种体内模型系统已证明，新生和成年乳腺组织在乳腺反应中对ERα使用不同的组织特异性作用。对乳腺增生组织中ERα和PR的免疫染色支持了以下观点：基质和上皮的ERα与上皮PR协同作用，控制成年小鼠的乳腺发育。
