Department of Molecular Genetics, The Ohio State University, Columbus, Ohio, USA.
The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
Endocr Relat Cancer. 2023 Nov 14;30(12). doi: 10.1530/ERC-23-0062. Print 2023 Dec 1.
Development of the mammary gland requires both proper hormone signaling and cross talk between the stroma and epithelium. While estrogen receptor (ERα) expression in the epithelium is essential for normal gland development, the role of this receptor in the stroma is less clear. Moreover, several lines of evidence suggest that mouse phenotypes of in utero exposure to endocrine disruption act through mesenchymal ERα in the developing fetus. We utilized a Twist2-cre mouse line to knock out mesenchymal ERα. Herein, we assessed mammary gland development in the context of mesenchymal ERα deletion. We also tested the effect of in utero bisphenol A (BPA) exposure to alter the tumor susceptibility in the mouse mammary tumor virus-neu (MMTV-neu) breast cancer mouse model. Mesenchymal ERα deletion resulted in altered reproductive tract development and atypical cytology associated with estrous cycling. The mammary gland demonstrated mature epithelial extension unlike complete ERα-knockout mice, but ductal extension was delayed and reduced compared to ERα-competent mice. Using the MMTV-Neu cancer susceptibility model, ERα-intact mice exposed to BPA had reduced tumor-free survival and overall survival compared to BPA-exposed mice having mesenchymal ERα deletion. This difference is specific for BPA exposure as vehicle-treated animals had no difference in tumor development between mice expressing and not expressing mesenchymal ERα. These data demonstrate that mesenchymal ERα expression is not required for ductal extension, nor does it influence cancer risk in this mouse model but does influence the cancer incidence associated with in utero BPA exposure.
乳腺的发育既需要适当的激素信号，也需要基质与上皮之间的串扰。虽然上皮细胞中的雌激素受体 (ERα) 表达对于正常的腺体发育是必不可少的，但该受体在基质中的作用还不太清楚。此外，有几条证据表明，胎儿期暴露于内分泌干扰物的小鼠表型是通过发育中的胎儿间充质 ERα 起作用的。我们利用 Twist2-cre 小鼠系敲除了间充质 ERα。在此，我们评估了在间充质 ERα 缺失的情况下乳腺的发育情况。我们还测试了胎儿期双酚 A (BPA) 暴露对改变小鼠乳腺肿瘤病毒 -neu (MMTV-neu) 乳腺癌小鼠模型中肿瘤易感性的影响。间充质 ERα 的缺失导致生殖道发育异常和与动情周期相关的非典型细胞学。与完全敲除 ERα 的小鼠不同，乳腺表现出成熟的上皮延伸，但与 ERα 功能正常的小鼠相比，导管延伸延迟且减少。使用 MMTV-Neu 癌症易感性模型，与未接受 BPA 暴露的 ERα 完整的小鼠相比，接受 BPA 暴露的小鼠的无肿瘤存活期和总存活期降低。这种差异是 BPA 暴露特异性的，因为在表达和不表达间充质 ERα 的小鼠中，载体处理的动物在肿瘤发展方面没有差异。这些数据表明，间充质 ERα 的表达对于导管延伸不是必需的，也不会影响该小鼠模型中的癌症风险，但会影响与胎儿期 BPA 暴露相关的癌症发病率。
