Abstract
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.
Highlights
Exposure to estrogen is a major risk factor for breast cancer
We initially used a human telomerase reverse transcriptase-immortalized human mammary epithelial cell line (HMEC) to determine whether estrogen receptor alpha (ERα) expression can inhibit premature cellular senescence induced by the expression of oncogenic H-ras-V12
human mammary epithelial cells (HMEC)/human telomerase reverse transcriptase (hTERT) cells were first transduced with an empty retrovirus or a retrovirus carrying an expression cassette of ERα and selected with puromycin
Summary
Exposure to estrogen is a major risk factor for breast cancer. About two-thirds of breast cancers are estrogen receptor alpha (ERα) positive [1]. High doses of synthetic estrogen were shown to inhibit tumor growth in patients with ER positive breast cancer [5]. These observations suggest that estrogen signaling appears growth-inhibitory in mammary epithelial cells. This scenario is inconsistent with the tumorigenesis-promoting activity of estrogen and ER. Cellular senescence is one of the mechanisms that normal cells use to avoid carcinogenesis [7].It was demonstrated that tamoxifen can induce a senescent phenotype in several ERα+ breast cancer cells lines [8], which suggested that ERα might play an important role in the regulation of senescence and growth inhibition in breast cancer
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