Liu Zhao, Wang Long, Yang Junhua, Bandyopadhyay Abhik, Kaklamani Virginia, Wang Shui, Sun Lu-Zhe
Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, Texas, United States of America.
Oncotarget. 2016 Jun 28;7(26):39097-39107. doi: 10.18632/oncotarget.9772.
Exposure to estrogen has long been associated with an increased risk of developing breast cancer. However, how estrogen signaling promotes breast carcinogenesis remains elusive. Senescence is known as an important protective response to oncogenic events. We aimed to elucidate the role of estrogen receptor alpha (ERα) on senescence in transformed human mammary epithelial cells and breast cancer cells. Our results show that ectopic expression of oncoprotein H-ras-V12 in immortalized human mammary epithelial cells (HMEC) significantly inhibited the phosphorylation of the retinoblastoma protein (Rb) and increased the activity of the senescence-associated beta-galactosidase (SA-β-Gal). These senescence-like phenotypes were reversed by ectopic expression of ERα. Similar inhibition of the H-ras-V12-induced SA-β-Gal activity by ERα was also observed in the human mammary epithelial MCF-10A cells. Co-expression of ERα and H-ras-V12 resulted in HMEC anchorage-independent growth in vitro and tumor formation in vivo. Furthermore, inhibition of ERα expression induced senescence-like phenotypes in ERα positive human breast cancer cells such as increased activity of SA-β-Gal, decreased phosphorylation of RB, and loss of mitogenic activity. Thus, the suppression of cellular senescence induced by oncogenic signals may be a major mechanism by which ERα promotes breast carcinogenesis.
长期以来，接触雌激素一直与患乳腺癌风险增加相关。然而，雌激素信号传导如何促进乳腺癌发生仍不清楚。衰老被认为是对致癌事件的一种重要保护反应。我们旨在阐明雌激素受体α（ERα）在转化的人乳腺上皮细胞和乳腺癌细胞衰老过程中的作用。我们的结果表明，在永生化人乳腺上皮细胞（HMEC）中异位表达癌蛋白H-ras-V12可显著抑制视网膜母细胞瘤蛋白（Rb）的磷酸化，并增加衰老相关β-半乳糖苷酶（SA-β-Gal）的活性。这些类似衰老的表型可通过ERα的异位表达得以逆转。在人乳腺上皮MCF-10A细胞中也观察到ERα对H-ras-V12诱导的SA-β-Gal活性有类似的抑制作用。ERα和H-ras-V12共表达导致HMEC在体外非锚定依赖性生长以及在体内形成肿瘤。此外，抑制ERα表达可在ERα阳性人乳腺癌细胞中诱导类似衰老的表型，如SA-β-Gal活性增加、RB磷酸化减少以及有丝分裂活性丧失。因此，致癌信号诱导的细胞衰老抑制可能是ERα促进乳腺癌发生的主要机制。
