Estrogen receptor alpha inhibits senescence-like phenotype and facilitates transformation induced by oncogenic ras in human mammary epithelial cells.
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.
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.|Department of Thyroid and Breast Surgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou, China.
Zhao
Z
Liu
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, Texas, United States of America.
Long
L
Wang
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, Texas, United States of America.
Junhua
J
Yang
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, Texas, United States of America.
Abhik
A
Bandyopadhyay
Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, Texas, United States of America.
Virginia
V
Kaklamani
Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Shui
S
Wang
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, Texas, United States of America.|Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, Texas, United States of America.
Lu-Zhe
LZ
Sun
D000818:Animals; D001940:Breast / Q000166:cytology*; D001943:Breast Neoplasms / Q000378:metabolism; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D004247:DNA / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009857:Oncogenes; D010641:Phenotype; D010766:Phosphorylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D014162:Transfection
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D004247:DNA; C501009:HRAS protein, human; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
Gerotarget; estrogen receptor alpha; ras; senescence; transformation