Altiok Nedret, Koyuturk Meral, Altiok Soner
Department of Pharmacology and Institute of Medical Sciences, Istanbul Science University Faculty of Medicine, Büyükdere Cad. No: 120, 34394, Esentepe-Istanbul, Turkey.
Breast Cancer Res Treat. 2007 Nov;105(3):247-54. doi: 10.1007/s10549-006-9451-1. Epub 2006 Dec 23.
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.
已知雌激素会刺激人类乳腺癌的发展。具有讽刺意味的是，高剂量雌激素可诱导绝经后女性激素依赖性乳腺癌消退。雌激素诱导乳腺癌肿瘤消退的机制仍不清楚。我们发现，在低生长刺激条件下，高浓度的17-β-雌二醇（雌二醇）可诱导雌激素受体（ER）阳性乳腺癌细胞系MCF-7发生凋亡，并伴随c-jun磷酸化增加，但在ER阴性乳腺癌细胞系MDA-MB 231中则不会，这表明这是一个由ER介导的事件。有趣的是，当c-jun氨基末端激酶（JNK）信号通路被JNK抑制剂SP600125阻断时，雌二醇抑制MCF-7细胞生长和诱导凋亡的能力被完全阻断。这些数据表明，JNK在介导高浓度雌二醇对MCF-7细胞的抗癌作用中起核心作用。我们的数据显示了在低生长刺激条件下雌二醇的凋亡作用，这提示了绝经后女性使用高剂量雌激素对乳腺癌进行药物控制的潜在意义。此外，我们的结果表明，增强JNK活性可能是治疗乳腺癌的一种有效的新方法。
