Segev D L, Ha T U, Tran T T, Kenneally M, Harkin P, Jung M, MacLaughlin D T, Donahoe P K, Maheswaran S
Pediatric Surgical Research Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
J Biol Chem. 2000 Sep 15;275(37):28371-9. doi: 10.1074/jbc.M004554200.
Müllerian inhibiting substance (MIS), a member of the transforming growth factor-beta superfamily, induces regression of the Müllerian duct in male embryos. In this report, we demonstrate MIS type II receptor expression in normal breast tissue and in human breast cancer cell lines, breast fibroadenoma, and ductal adenocarcinomas. MIS inhibited the growth of both estrogen receptor (ER)-positive T47D and ER-negative MDA-MB-231 breast cancer cell lines, suggesting a broader range of target tissues for MIS action. Inhibition of growth was manifested by an increase in the fraction of cells in the G(1) phase of the cell cycle and induction of apoptosis. Treatment of breast cancer cells with MIS activated the NFkappaB pathway and selectively up-regulated the immediate early gene IEX-1S, which, when overexpressed, inhibited breast cancer cell growth. Dominant negative IkappaBalpha expression ablated both MIS-mediated induction of IEX-1S and inhibition of growth, indicating that activation of the NFkappaB signaling pathway was required for these processes. These results identify the NFkappaB-mediated signaling pathway and a target gene for MIS action and suggest a putative role for the MIS ligand and its downstream interactors in the treatment of ER-positive as well as negative breast cancers.
苗勒管抑制物质（MIS）是转化生长因子-β超家族的成员之一，可诱导雄性胚胎中的苗勒管退化。在本报告中，我们证明了MIS II型受体在正常乳腺组织、人乳腺癌细胞系、乳腺纤维腺瘤和导管腺癌中的表达。MIS抑制雌激素受体（ER）阳性的T47D和ER阴性的MDA-MB-231乳腺癌细胞系的生长，这表明MIS作用的靶组织范围更广。生长抑制表现为细胞周期G(1)期细胞比例增加和细胞凋亡诱导。用MIS处理乳腺癌细胞可激活NFκB通路并选择性上调即刻早期基因IEX-1S，IEX-1S过表达时可抑制乳腺癌细胞生长。显性负性IκBα表达消除了MIS介导的IEX-1S诱导和生长抑制，表明这些过程需要NFκB信号通路的激活。这些结果确定了NFκB介导的信号通路和MIS作用的一个靶基因，并提示MIS配体及其下游相互作用分子在ER阳性和阴性乳腺癌治疗中的假定作用。
