Dual function of ERRαin breast cancer and bone metastasis formation:implication of VEGF and osteoprotegerin
Menée à l'aide de xénogreffes, cette étude identifie le double rôle joué par le récepteur ERR
Bone metastasis are a complication occurring in up to 70 percent of advanced breast cancer patients. The estrogen receptor related receptor alpha (ERRα) has been implicated in breast cancer and bone development, prompting us to examine whether ERRα may function in promoting the osteolytic growth of breast cancer cells in bone. In a mouse xenograft model of metastatic human breast cancer over-expression of wild-type ERRα reduced metastasis whereas overexpression of a dominant negative mutant promoted metastasis. Osteoclasts were directly affected and ERRα upregulated the osteoclastogenesis inhibitor, osteoprotegerin (OPG), providing a direct mechanistic basis for understanding how ERRα reduced breast cancer cell growth in bone. In contrast, ERRα overexpression increased breast cancer cell growth in the mammary gland. ERRα -overexpressing primary tumors were highly vascularized, consistent with an observed upregulation of angiogenic growth factor, the vascular endothelial growth factor (VEGF). In support of these findings, we documented that elevated expression of ERRα mRNA in breast carcinomas was associated with high expression of OPG and VEGF and with disease progression. In conclusion, our results demonstrate that ERRα 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 Research 2011