Dual Function of ERRα in Breast Cancer and Bone Metastasis Formation: Implication of VEGF and Osteoprotegerin

Abstract

Bone metastasis is a complication occurring in up to 70% of advanced breast cancer patients. The estrogen receptor-related receptor alpha (ERRa) has been implicated in breast cancer and bone development, prompting us to examine whether ERRa may function in promoting the osteolytic growth of breast cancer cells in bone. In a mouse xenograft model of metastatic human breast cancer, overexpression of wild-type ERRa reduced metastasis, whereas overexpression of a dominant negative mutant promoted metastasis. Osteoclasts were directly affected and ERRa upregulated the osteoclastogenesis inhibitor, osteoprotegerin (OPG), providing a direct mechanistic basis for understanding how ERRa reduced breast cancer cell growth in bone. In contrast, ERRa overexpression increased breast cancer cell growth in the mammary gland. ERRa-overexpressing primary tumors were highly vascularized, consistent with an observed upregulation of angiogenic growth factor, the VEGF. In support of these findings, we documented that elevated expression of ERRa mRNA in breast carcinomas was associated with high expression of OPG and VEGF and with disease progression. In conclusion, our results show that ERRa plays a dual role in breast cancer progression in promoting the local growth of tumor cells, but decreasing metastatic growth of osteolytic lesions in bone. Cancer Res; 71(17); 5728-38. Ó2011 AACR.

Estrogen-related receptor α decreases RHOA stability to induce orientated cell migration

“…These include breast cancers, where a regulatory loop involving ERBB2 signaling has been documented (27,46,47). In addition ERRα promotes angiogenesis likely via the regulation of VEGF expression (28,30). Several reports have shown that ERRα is instrumental in controlling energy metabolism in tissues such as the liver, heart, or skeletal muscle through regulation of mitochondrial biogenesis, oxidative phosphorylation, glycolysis, pyruvate metabolism, and the TCA cycle (18,19,48).…”

“…Moreover ablation of ERRα in knock-out mice delays ERBB2-induced mammary gland tumorigenesis (27). Furthermore overexpression of ERRα in xenografted breast cancer cells increases their metastatic capacities (28), in correlation with a massive induction Significance Several developmental and physiological processes require that cells display a controlled ability to migrate in an orientated manner. This capacity is also reacquired by certain cancer cells during their progression toward aggressiveness that allows them to establish distant metastases.…”

The emerging roles of orphan nuclear receptors in prostate cancer

“…Much attention has been paid to the role of ERRα in breast cancer due to its close relationship with ERs. Functional analyses performed on cancer cells suggest that ERRα can play regulatory roles in cancer growth through different mechanisms, including modulation of estrogen synthesis [66], cross-talks with pathways mediated by other hormone receptors (ERα, AR and GR) [52,64,67,68], enhancement of HIF-1 signaling [56], promotion of tumor aggressiveness by decreases the stability and activity of the RHOA protein [69] and tumor angiogenesis by targeting to VEGF gene [70][71][72] and induction of endothelial nitric oxide synthase (eNOS) expression [73], activation of oncogene ERBB2 or HER2 signaling [68] and mediation of oncogenic Ras-dependent anchorageindependent growth [74]. However, the functional role of ERRα in prostate cancer is still far from clear.…”

Estrogen-related receptor α participates transforming growth factor-β (TGF-β) induced epithelial-mesenchymal transition of osteosarcoma cells

“…Studies indicated that over expression of ERRa in xenografted breast cancer cells increases their metastatic capacities. 1,10,24 The expression of ERRa is highly detected in osteoblastic cells. 4 Further, it can confer methotrexate resistance via attenuation of reactive oxygen species (ROS) production in OS cells.…”