Department of Physiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA,
Horm Cancer. 2013 Dec;4(6):381-90. doi: 10.1007/s12672-013-0159-5. Epub 2013 Aug 31.
Progestins are reported to increase the risk of more aggressive estrogen receptor positive, progesterone receptor positive (ER+ PR+) breast cancers in postmenopausal women. Using an in vivo rat model of ER+ PR + mammary cancer, we show that tumors arising in the presence of estrogen and progesterone exhibit increased proliferation and decreased nuclear expression of the cell cycle inhibitor p27 compared with tumors growing in the presence of estrogen alone. In human T47D breast cancer cells, progestin increased proliferation and decreased nuclear p27 expression. The decrease of nuclear p27 protein was dependent on activation of Src and PI3K by progesterone receptor isoforms PRA or PRB. Importantly, increased proliferation and decreased nuclear p27 expression were observed in invasive breast carcinoma compared with carcinoma in situ. These results suggest that progesterone specifically regulates intracellular localization of p27 protein and proliferation. Therefore, progesterone-activated pathways can provide useful therapeutic targets for treatment of more aggressive ER+ PR+ breast cancers.
孕激素被报道会增加绝经后妇女中更具侵袭性的雌激素受体阳性、孕激素受体阳性（ER+ PR+）乳腺癌的风险。我们使用 ER+ PR+ 乳腺肿瘤的体内大鼠模型表明，与仅在雌激素存在下生长的肿瘤相比，在雌激素和孕激素存在下发生的肿瘤表现出增殖增加和细胞周期抑制剂 p27 的核表达减少。在人 T47D 乳腺癌细胞中，孕激素增加了增殖并降低了核 p27 的表达。核 p27 蛋白的减少依赖于孕激素受体亚型 PRA 或 PRB 激活Src 和 PI3K。重要的是，与原位癌相比，浸润性乳腺癌中观察到增殖增加和核 p27 表达减少。这些结果表明，孕激素特异性调节 p27 蛋白的细胞内定位和增殖。因此，孕激素激活的途径可以为治疗更具侵袭性的 ER+ PR+ 乳腺癌提供有用的治疗靶点。
