Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Department of Comparative Biosciences, University Wisconsin-Madison, Madison, Wisconsin, USA.
FASEB J. 2019 Jul;33(7):8623-8633. doi: 10.1096/fj.201802347RRR. Epub 2019 Apr 19.
Aromatase inhibitors are the preferred treatment for certain women with estrogen receptor (ER)-positive breast cancer, but evidence suggests that women with obesity experience aromatase inhibitor resistance at higher rates. To compare how stromal cells derived from women who are lean or obese influence response to the aromatase inhibitor (anastrazole), we incorporated patient-derived stroma in a previously characterized MCF7-derived duct model. Coculture with adipose stromal cells enabled the metabolism of testosterone (T) to E, which induced estrogen response element activity, epithelial proliferation, and hyperplasia in MCF7 cells. The effects of T were inhibited by the ER antagonist tamoxifen and aromatase inhibitor anastrazole and were increased by the aromatase inducer dexamethasone. Primary mammary adipose stromal cells derived from women with obesity displayed increased aromatase mRNA compared with lean controls. MCF7-derived ducts cocultured with obese stromal cells exhibited higher maximal aromatization-induced ER transactivation and reduced anastrazole sensitivity, a difference not seen in 2-dimensional coculture. Finally, tamoxifen was more effective than anastrazole at reducing aromatization-induced ER transactivation and proliferation. These findings suggest that patient-specific responses to hormone therapies can be modeled and studied organotypically and add to evidence advocating obesity as a parameter to consider when identifying treatments for patients with ER-positive breast cancer.-Morgan, M. M., Arendt, L. M., Alarid, E. T., Beebe, D. J., Johnson, B. P. Mammary adipose stromal cells derived from obese women reduce sensitivity to the aromatase inhibitor anastrazole in an organotypic breast model.
芳香酶抑制剂是治疗雌激素受体（ER）阳性乳腺癌的首选药物，但有证据表明，肥胖女性对芳香酶抑制剂的耐药性更高。为了比较来自肥胖和消瘦女性的基质细胞如何影响对芳香酶抑制剂（阿那曲唑）的反应，我们将患者来源的基质细胞纳入先前表征的 MCF7 衍生的导管模型中。与脂肪基质细胞共培养可使睾酮（T）代谢为 E，从而诱导 MCF7 细胞中的雌激素反应元件活性、上皮增殖和增生。T 的作用被 ER 拮抗剂他莫昔芬和芳香酶抑制剂阿那曲唑抑制，并被芳香酶诱导剂地塞米松增强。与瘦对照组相比，来自肥胖女性的原发性乳腺脂肪基质细胞显示出更高的芳香酶 mRNA。与肥胖基质细胞共培养的 MCF7 衍生导管表现出更高的最大芳香化诱导的 ER 转激活和降低的阿那曲唑敏感性，而在 2 维共培养中未观察到这种差异。最后，与阿那曲唑相比，他莫昔芬在降低芳香化诱导的 ER 转激活和增殖方面更有效。这些发现表明，可以对激素治疗的患者特异性反应进行建模和器官型研究，并为肥胖作为识别 ER 阳性乳腺癌患者治疗方法的一个参数提供了更多证据。
