Takahashi Mina, Otsuka Fumio, Miyoshi Tomoko, Otani Hiroyuki, Goto Junko, Yamashita Misuzu, Ogura Toshio, Makino Hirofumi, Doihara Hiroyoshi
Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama City 700-8558, Japan.
J Endocrinol. 2008 Dec;199(3):445-55. doi: 10.1677/JOE-08-0226. Epub 2008 Sep 9.
Estrogen is involved in the development and progression of breast cancer. Here, we investigated the effects of bone morphogenetic proteins (BMPs) on breast cancer cell proliferation caused by estrogen using human breast cancer MCF-7 cells. MCF-7 cells express estrogen receptors (ESR1 and ESR2), BMP receptors, and SMAD signaling molecules. Estradiol and membrane-impermeable estradiol stimulated MCF-7 cell proliferation. Estradiol also reduced mRNA levels of ESR1, aromatase, and steroid sulfatase. Treatment with BMPs and activin had no effects on MCF-7 cell proliferation. However, BMP2, BMP4, BMP6, BMP7, and activin suppressed estradiol-induced cell mitosis, with the effects of BMP6, BMP7, and activin being more prominent than those of BMP2 and BMP4. Activin decreased ESR1 mRNA expression, while BMP6 and BMP7 impaired steroid sulfatase expression in MCF-7 cells. Interestingly, SMAD1,5,8 activation elicited by BMP6 and BMP7, but not by BMP2 and BMP4, was preserved even under the exposure of a high concentration of estradiol. The difference of BMP responsiveness was likely due to the differential modulation of BMP receptor expression induced by estradiol. In this regard, estradiol decreased the expression levels of BMPR1A, BMPR1B, ACVR2A, and ACVR2B but did not affect ACVR1 and BMPRII, leading to the sustained effects of BMP6 and BMP7 in estrogen-treated MCF-7 cells. Estradiol rapidly activated MAPK phosphorylation including extracellular signal-regulated kinase 1/2, p38, and stress-activated protein kinase/c-Jun NH2-terminal kinase pathways and BMP6, BMP7, and activin preferentially inhibited estradiol-induced p38 phosphorylation. SB203580, a selective p38 MAPK inhibitor effectively suppressed estradiol-induced cell mitosis, suggesting that p38 MAPK plays a key role in estrogen-sensitive breast cancer cell proliferation. Thus, a novel interrelationship between estrogen and the breast cancer BMP system was uncovered, in which inhibitory effects of BMP6 and BMP7 on p38 signaling and steroid sulfatase expression were functionally involved in the suppression of estrogen-induced mitosis of breast cancer cells.
雌激素参与乳腺癌的发生和发展。在此，我们使用人乳腺癌MCF-7细胞研究了骨形态发生蛋白（BMPs）对雌激素引起的乳腺癌细胞增殖的影响。MCF-7细胞表达雌激素受体（ESR1和ESR2）、BMP受体和SMAD信号分子。雌二醇和膜不可渗透的雌二醇刺激MCF-7细胞增殖。雌二醇还降低了ESR1、芳香化酶和类固醇硫酸酯酶的mRNA水平。用BMPs和激活素处理对MCF-7细胞增殖没有影响。然而，BMP2、BMP4、BMP6、BMP7和激活素抑制雌二醇诱导的细胞有丝分裂，其中BMP6、BMP7和激活素的作用比BMP2和BMP4更显著。激活素降低ESR1 mRNA表达，而BMP6和BMP7损害MCF-7细胞中类固醇硫酸酯酶的表达。有趣的是，即使在高浓度雌二醇暴露下，BMP6和BMP7引起的SMAD1、5、8激活仍得以保留，而BMP2和BMP4则不能。BMP反应性的差异可能是由于雌二醇诱导的BMP受体表达的差异调节。在这方面，雌二醇降低了BMPR1A、BMPR1B、ACVR2A和ACVR2B的表达水平，但不影响ACVR1和BMPRII，从而导致BMP6和BMP7在雌激素处理的MCF-7细胞中产生持续作用。雌二醇迅速激活包括细胞外信号调节激酶1/2、p38和应激激活蛋白激酶/c-Jun NH2末端激酶途径在内的MAPK磷酸化，而BMP6、BMP7和激活素优先抑制雌二醇诱导的p38磷酸化。选择性p38 MAPK抑制剂SB203580有效抑制雌二醇诱导的细胞有丝分裂，表明p38 MAPK在雌激素敏感的乳腺癌细胞增殖中起关键作用。因此，揭示了雌激素与乳腺癌BMP系统之间一种新的相互关系，其中BMP6和BMP7对p38信号传导和类固醇硫酸酯酶表达的抑制作用在功能上参与了对雌激素诱导的乳腺癌细胞有丝分裂的抑制。
