The orphan nuclear receptor LRH-1 promotes breast cancer motility and invasion
The orphan nuclear receptor LRH-1 promotes breast cancer motility and invasion
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DOI：
10.1677/erc-10-0179
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发表时间：
2010-12-01
影响因子：
3.9
通讯作者：
Clyne, C. D.
中科院分区：
文献类型：
--
作者：
Chand, A. L.;Herridge, K. A.;Clyne, C. D.
孤儿核受体肝受体同源物-1（LRH-1）在发育、胆固醇和胆汁酸稳态以及类固醇生成中发挥作用。它还增强癌细胞的增殖和细胞周期进展。在乳腺癌中，LRH-1表达与浸润性乳腺癌相关;与ER α状态和芳香化酶活性呈正相关;并促进雌激素依赖性细胞增殖。然而，LRH-1在乳腺癌上皮细胞中的作用机制仍不清楚。通过在ER阳性的MCF-7和ER阴性的MDA-MB-231乳腺癌细胞中沉默或过表达LRH-1，我们已经证明LRH-1促进运动性和细胞侵袭力。在非致瘤性乳腺上皮细胞系MCF-10A中观察到类似的作用。肌动蛋白细胞骨架和E-钙粘蛋白裂解的重塑与LRH-1过表达，有助于增加迁移和侵袭性。此外，在LRH-1过表达细胞中，观察到120 kDa E-钙粘蛋白被截短为无活性的97 kDa形式。E-钙粘蛋白的这些翻译后修饰可能与基质金属蛋白酶9表达的LRH-1依赖性变化有关。这些发现表明LRH-1在促进乳腺癌迁移和侵袭中的新作用，独立于雌激素敏感性。因此，LRH-1可能代表乳腺癌治疗的新靶点。内分泌相关癌症（2010年）17 965-975
The orphan nuclear receptor liver receptor homologue-1 (LRH-1) has roles in the development, cholesterol and bile acid homeostasis, and steroidogenesis. It also enhances proliferation and cell cycle progression of cancer cells. In breast cancer, LRH-1 expression is associated with invasive breast cancer; positively correlates with ER alpha status and aromatase activity; and promotes oestrogen-dependent cell proliferation. However, the mechanism of action of LRH-1 in breast cancer epithelial cells is still not clear. By silencing or over-expressing LRH-1 in ER-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cells, we have demonstrated that LRH-1 promotes motility and cell invasiveness. Similar effects were observed in the non-tumourigenic mammary epithelial cell line, MCF-10A. Remodelling of the actin cytoskeleton and E-cadherin cleavage was observed with LRH-1 over-expression, contributing to increased migratory and invasive properties. Additionally, in LRH-1 over-expressing cells, the truncation of the 120 kDa E-cadherin to the inactive 97 kDa form was observed. These post-translational modifications in E-cadherin may be associated with LRH-1-dependent changes to matrix metalloproteinase 9 expression. These findings suggest a new role of LRH-1 in promoting migration and invasion in breast cancer, independent of oestrogen sensitivity. Therefore, LRH-1 may represent a new target for breast cancer therapeutics. Endocrine-Related Cancer (2010) 17 965-975