Inhibition of skeletal metastasis by ectopic ERα expression in ERα-negative human breast cancer cell lines

Some hormone-independent breast cancers lack functional estrogen receptors (ERs) and show evidence of a more aggressive metastatic phenotype. A protective role of the ER has also been suggested in hormone-resistant breast cancer progression. In this study, we have investigated the effect of the ectopic expression of human ER alpha on the bone-metastatic potential of highly metastatic ER alpha-negative human breast cancer MDA-MB-231 and MDA-MB-435-F-L cell lines in an experimental model of bone metastasis in nude mice. ER alpha overexpression had no effect on the growth of both cell lines but reduced the expression of integrin alpha(v)beta(3) and the receptor activator of NF-kappa B, which are known to promote bone metastasis. A significant reduction in the incidence of osteolytic bone metastasis was observed by X-ray imaging of the legs and arms of mice inoculated with ER alpha-expressing clones of MDA-MB-231 cells in comparison to controls. Ectopic expression of ER alpha in MDA-MB-435-F-L cells also reduced their widespread skeletal metastasis to the legs, arms, spine, and mandible, as detected by whole-mouse enhanced green fluorescent protein imaging. Our study indicates for the first time that stable reintroduction of functional ER alpha in ER alpha-negative human breast cancer cells can inhibit their aggressive bone-metastatic potential in an experimental bone metastasis model.