Regulation of estrogenic effects by beclin 1 in breast cancer cells.
Beclin 1 is an essential mediator of autophagy and a regulator of cell growth and cell death. We examined the effect of Beclin 1 overexpression on the action of estradiol (E(2)) and two antiestrogens, raloxifene and 4-hydroxytamoxifen, in estrogen receptor alpha (ERalpha)-positive MCF-7 breast cancer cells. [(3)H]-thymidine incorporation studies showed that Beclin 1-overexpressing cells (MCF-7 x beclin) had a lower proliferative response to E(2) compared with cells transfected with vector control (MCF-7 x control). There was only a 35% increase in [(3)H]-thymidine incorporation, after 24 hours of E(2) treatment of MCF-7 x beclin cells compared with untreated cells, whereas this increase was 2-fold for MCF-7 x control cells. E(2)-induced changes in the expression of early-response genes were examined by real-time quantitiative PCR. There were significant differences in the pattern of expression of E(2)-induced genes c-myc, c-fos, Erg-1, and Nur77 between MCF-7 x beclin and MCF-7 x control cells two hours after treatment. Although E(2)-induced growth of MCF-7 x control cells was completely inhibited by 500 nmol/L raloxifene or 500 nmol/L 4-hydroxytamoxifen, these concentrations of antiestrogens had no significant effect on the growth of MCF-7 x beclin cells. Confocal microscopic and coimmunoprecipitation studies showed evidence for colocalization and association of Beclin 1 and ERalpha. In addition, E(2) caused a decrease in Akt phosphorylation in MCF-7 x beclin cells, compared with a 3-fold increase in MCF-7 cells, five minutes after treatment. These results indicate that Beclin 1 can down-regulate estrogenic signaling and growth response, and contribute to the development of antiestrogen resistance. This observation might be useful to define and overcome antiestrogen resistance of breast cancer.
John
Shali
S
Departments of Medicine, Environmental and Occupational Medicine, University of Medicine and Dentistry, New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
Nayvelt
Irina
I
Hsu
Hui-Chen
HC
Yang
PingAr
P
Liu
Wensheng
W
Das
Gokul M
GM
Thomas
Thresia
T
Thomas
T J
TJ
D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000071186:Beclin-1; D001943:Breast Neoplasms / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014018:Tissue Distribution / Q000187:drug effects; D014407:Tumor Cells, Cultured
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D008565:Membrane Proteins; D020849:Raloxifene Hydrochloride; D004958:Estradiol