OPG-Fc inhibits ovariectomy-induced growth of disseminated breast cancer cells in bone

Abstract

Dormant disseminated tumour cells can be detected in the bone marrow of breast cancer patients several years after resection of the primary tumour. The majority of these patients will remain asymptomatic, however, ∼15% will go on to develop overt bone metastases and this condition is currently incurable. The reason why these dormant cells are stimulated to proliferate and form bone tumours in some patients and not others remains to be elucidated. We have recently shown that in an in vivo model, increasing bone turnover by ovariectomy stimulated proliferation of disseminated tumour cells, resulting in formation of bone metastasis. We now show for the first time that osteoclast mediated mechanisms induce growth of tumours from dormant MDA-MB-231 cells disseminated in the bone. We also show that disruption of RANK-RANKL interactions following administration of OPG-Fc inhibits growth of these dormant tumour cells in vivo. Our data support early intervention with anti-resorptive therapy in a low-oestrogen environment to prevent development of bone metastases. What's new? Dormant disseminated tumour cells can be detected in the bone marrow of breast cancer patients several years after resection of the primary tumour. The reason why dormant cells are stimulated to proliferate and form bone tumours in some patients and not others remains unclear. The authors show for the first time that osteoclast-mediated mechanisms induce tumour growth from dormant tumor cells disseminated in bone. Administration of OPG-Fc, a potent osteoclastogenesis inhibitor disrupting RANK-RANKL interactions, inhibits dormant tumour cell growth in vivo. The data support the early administration of anti-resorptive therapy in a low-oestrogen setting to prevent development of bone metastases.