The orphan nuclear receptor LRH-1 promotes breast cancer motility and invasion.
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 ERα 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.
Chand
A L
AL
Cancer Drug Discovery Laboratory, Prince Henry's Institute, 246 Clayton Road, Melbourne, Victoria 3168, Australia. ashwini.chand@princehenrys.org
Herridge
K A
KA
Thompson
E W
EW
Clyne
C D
CD
D000704:Analysis of Variance; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics*; D011499:Protein Processing, Post-Translational; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D015820:Cadherins; D047628:Estrogen Receptor alpha; C082631:NR5A2 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D020780:Matrix Metalloproteinase 9