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 ERα on the bone-metastatic potential of highly metastatic ERα-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. ERα overexpression had no effect on the growth of both cell lines but reduced the expression of integrin α_vβ₃ and the receptor activator of NF-κB, 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 ERα-expressing clones of MDA-MB-231 cells in comparison to controls. Ectopic expression of ERα 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 ERα in ERα-negative human breast cancer cells can inhibit their aggressive bone-metastatic potential in an experimental bone metastasis model.