Endocrine Abstracts

Estrogen action is involved in the development and progression of breast cancer. In the present study, we studied the effects of bone morphogenetic proteins (BMPs) on breast cancer cell proliferation induced by estrogen using human breast cancer MCF-7 cells. MCF-7 cells express estrogen receptors (ER)α and β, BMP receptors, and Smad signaling molecules. Estradiol and membrane-impermeable estradiol stimulated MCF-7 cell proliferation. Estradiol also reduced mRNA levels of ERα, aromatase and steroid sulfatase. Treatment with BMPs and activin had no effects on MCF-7 cell proliferation. However, BMP-2, -4, -6, -7 and activin suppressed estradiol-induced cell mitosis, with the effects of BMP-6, -7 and activin being more prominent than those of BMP-2 and -4. Activin decreased ERα mRNA expression, while BMP-6 and -7 impaired steroid sulfatase expression in MCF-7 cells. Interestingly, Smad1, 5, 8 activation elicited by BMP-6 and -7, but not by BMP-2 and -4, was preserved even under the exposure of 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 ALK-3, -6, ActRII and ActRIIB but did not affect ALK-2 and BMPRII, leading to the sustained effects of BMP-6 and -7 in estrogen-treated MCF-7 cells. Estradiol rapidly activated MAPK phosphorylation including ERK1/ERK2, p38 and SAPK/JNK pathways and BMP-6, -7 and activin preferentially inhibited estraidol-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 BMP-6 and -7 on p38 signaling and steroid sulfatase expression were functionally involved in the suppression of estrogen-induced mitosis of breast cancer cells.