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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-08-0226v1 199/3/445    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Takahashi, M. Articles by Doihara, H. Search for Related Content PubMed PubMed Citation Articles by Takahashi, M. Articles by Doihara, H.

M Takahashi, Cancer and Thoracic Surgery, Okayama University Graduate School, Okayama, Japan
F Otsuka, Medicine and Clinical Science, Okayama University Graduate School, Okayama-city, 700-8558, Japan
T Miyoshi, Medicine and Clinical Science, Okayama University Graduate School, Okayama, Japan
H Otani, Medicine and Clinical Science, Okayama University Graduate School, Okayama, Japan
J Goto, Medicine and Clinical Science, Okayama University Graduate School, Okayama, Japan
M Yamashita, Medicine and Clinical Science, Okayama University Graduate School, Okayama, Japan
T Ogura, Medicine and Clinical Science, Okayama University Graduate School, Okayama, Japan
H Makino, Medicine and Clinical Science, Okayama University Graduate School, Okayama, Japan
H Doihara, Cancer and Thoracic Surgery, Okayama University Graduate School, Okayama, Japan

Correspondence: Fumio Otsuka, Email: fumiotsu{at}md.okayama-u.ac.jp

Abstract

Estrogen is involved in the development and progression of breast cancer. Here we investigated the effects of BMP on breast cancer cell proliferation caused by estrogen using human MCF-7 cells. MCF-7 cells express ERalpha/beta, BMPR and Smads. Estradiol and membrane-impermeable estradiol stimulated MCF-7 cell proliferation. Estradiol also reduced mRNA levels of ERalpha, aromatase and steroid sulfatase. Treatment with BMP/activin had no effects on MCF-7 cell proliferation. However, BMP/activin suppressed estradiol-induced cell mitosis, with the effects of BMP-6/7 and activin being more prominent than those of BMP-2/4. Activin decreased ERalpha mRNA expression, while BMP-6/7 impaired steroid sulfatase expression in MCF-7 cells. Interestingly, Smad1,5,8 activation elicited by BMP-6/7, but not by BMP-2/4, was preserved even under the exposure of high concentration of estradiol. The difference of BMP responsiveness was likely due to the differential modulation of BMPR 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-6/7 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-6/7 on p38 signaling and steroid sulfatase expression were functionally involved in the suppression of estrogen-induced mitosis of breast cancer cells.

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