Estrogen receptor alpha inhibits senescence-like phenotype and facilitates transformation induced by oncogenic ras in human mammary epithelial cells.
Estrogen receptor alpha inhibits senescence-like phenotype and facilitates transformation induced by oncogenic ras in human mammary epithelial cells.
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DOI：
10.18632/oncotarget.9772
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发表时间：
2016-06-28
期刊：
影响因子：
--
通讯作者：
Sun LZ
中科院分区：
文献类型：
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作者：
Liu Z;Wang L;Yang J;Bandyopadhyay A;Kaklamani V;Wang S;Sun LZ
长期以来，接触雌激素一直与患乳腺癌的风险增加有关。然而，雌激素信号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重要保护反应。我们的目的是阐明雌激素受体α（ERα）对转化的人乳腺上皮细胞和乳腺癌细胞衰老的作用。我们的结果表明，永生化人乳腺上皮细胞（HMEC）中癌蛋白H-ras-V12的异位表达显着抑制了视网膜母细胞瘤蛋白（Rb）的磷酸化，并增加了衰老相关β-半乳糖苷酶（SA-β-Gal）的活性。这些衰老样表型被 ERα 的异位表达逆转。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 活性的类似抑制。 ERα 和 H-ras-V12 的共表达导致 HMEC 体外贴壁独立生长和体内肿瘤形成。此外，抑制 ERα 表达会诱导 ERα 阳性人乳腺癌细胞出现衰老样表型，例如 SA-β-Gal 活性增加、RB 磷酸化降低以及促有丝分裂活性丧失。因此，抑制致癌信号诱导的细胞衰老可能是ERα促进乳腺癌发生的主要机制。
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.