JNK pathway regulates estradiol-induced apoptosis in hormone-dependent human breast cancer cells.
Estrogen is known to stimulate breast cancer development in humans. Ironically, high doses of estrogen can induce regression of hormone-dependent breast cancer in postmenopausal women. The mechanism by which estrogen induces tumour regression in breast cancer is still unknown. We found that under low growth-stimulated conditions, high concentrations of 17-beta-estradiol (estradiol) induces apoptosis and concomitantly increases phosphorylation of c-jun in estrogen receptor (ER)-positive breast cancer cell line, MCF-7, but not in ER-negative breast cancer cell line MDA-MB 231 suggesting an ER-mediated event. Interestingly, when the c-jun NH2-terminal kinase (JNK) signalling pathway was disrupted by the JNK inhibitor SP600125, the ability of estradiol to inhibit the growth of MCF-7 cells and to induce apoptosis was completely blocked. These data suggest that JNK plays a central role in mediating the anticancer effect of high concentrations of estradiol in MCF-7 cells. Our data showing the apoptotic effect of estradiol in low growth-stimulated conditions suggest potential implications for the pharmacological control of breast cancer with high dose estrogen in postmenopausal women. Furthermore, our results indicate that augmenting JNK activity could be an efficient novel approach for treating breast cancer.
Altiok
Nedret
N
Department of Pharmacology and Institute of Medical Sciences, Istanbul Science University Faculty of Medicine, Büyükdere Cad. No: 120, 34394, Esentepe-Istanbul, Turkey. naltiok@superonline.com
Koyuturk
Meral
M
Altiok
Soner
S
D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D004789:Enzyme Activation; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D004967:Estrogens; D016159:Tumor Suppressor Protein p53; D004958:Estradiol; D048031:JNK Mitogen-Activated Protein Kinases