ERRα Expression in Bone Metastases Leads to an Exacerbated Antitumor Immune Response

Bone is the most common metastatic site for breast cancer. Although the estrogen-related receptor alpha (ERR alpha) has been implicated in breast cancer cell dissemination to the bone from the primary tumor, its role after tumor cell anchorage in the bone microenvironment remains elusive. Here, we reveal that ERR alpha inhibits the progression of bone metastases of breast cancer cells by increasing the immune activity of the bone microenvironment. Overexpression of ERR alpha in breast cancer bone metastases induced expression of chemokines CCL17 and CCL20 and repressed production of TGF beta 3. Subsequently, CD8(+) T lymphocytes recruited to bone metastases escaped TGF beta signaling control and were endowed with exacerbated cytotoxic features, resulting in significant reduction in metastases. The clinical relevance of our findings in mice was confirmed in over 240 patients with breast cancer. Thus, this study reveals that ERR alpha regulates immune properties in the bone microenvironment that contributes to decreasing metastatic growth. Significance This study places ERR alpha at the interplay between the immune response and bone metastases of breast cancer, highlighting a potential target for intervention in advanced disease.