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 (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, overexpression 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 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 show 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.

• Authors: Anaïs Fradet, Helène Sorel, Lamia Bouazza, Delphine Goehrig, Baptiste Dépalle, Akeila Bellahcène, Vincent Castronovo, Hélène Follet, Françoise Descotes, Jane E Aubin, Philippe Clézardin, Edith Bonnelye
• Journal: Cancer research (Cancer Res) Vol. 71 Issue 17 Pg. 5728-38 (Sep 01 2011) ISSN: 1538-7445 [Electronic] United States
• PMID: 21734015 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Osteoprotegerin
• Receptors, Estrogen
• TNFRSF11B protein, human
• VEGFA protein, human
• Vascular Endothelial Growth Factor A

Topics

• Animals
• Bone Neoplasms (metabolism, mortality, secondary)
• Breast Neoplasms (blood supply, metabolism, pathology)
• Carcinoma (blood supply, metabolism, secondary)
• Cell Line, Tumor
• Female
• Humans
• Mice
• Mice, Inbred BALB C
• Neovascularization, Pathologic (genetics, metabolism)
• Osteoprotegerin (metabolism)
• Receptors, Estrogen (biosynthesis, genetics)
• Vascular Endothelial Growth Factor A (metabolism)
• Xenograft Model Antitumor Assays
• ERRalpha Estrogen-Related Receptor