Research Papers: Gerotarget (Focus on Aging):

Estrogen receptor alpha inhibits senescence-like phenotype and facilitates transformation induced by oncogenic ras in human mammary epithelial cells

Zhao Liu, Long Wang, Junhua Yang, Abhik Bandyopadhyay, Virginia Kaklamani, Shui Wang _ and Lu-Zhe Sun

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Oncotarget. 2016; 7:39097-39107. https://doi.org/10.18632/oncotarget.9772

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Zhao Liu1,2,4, Long Wang2, Junhua Yang2, Abhik Bandyopadhyay2, Virginia Kaklamani3, Shui Wang1 and Lu-Zhe Sun2,3

1 Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

2 Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, Texas, United States of America

3 Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, Texas, United States of America

4 Department of Thyroid and Breast Surgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou, China

Correspondence to:

Shui Wang, email:

Lu-Zhe Sun, email:

Keywords: estrogen receptor alpha; senescence; transformation; ras; Gerotarget

Received: November 18, 2015 Accepted: May 20, 2016 Published: June 01, 2016


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.

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