ERRa expression in bone metastases leads to an exacerbated antitumor immune response

Abstract

Bone is the most common metastatic site for breast cancer. Although the estrogen-related receptor alpha (ERRa) 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 ERRa inhibits the progression of bone metastases of breast cancer cells by increasing the immune activity of the bone microenvironment. Overexpression of ERRa in breast cancer bone metastases induced expression of chemokines CCL17 and CCL20 and repressed production of TGFb3. Subsequently, CD8þ T lymphocytes recruited to bone metastases escaped TGFb 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 ERRa regulates immune properties in the bone microenvironment that contributes to decreasing metastatic growth.