A novel orthotopic model of breast cancer metastasis to bone

Breast cancer affects approximately one woman in twelve and kills more wome n than any other cancer. If detected early, patients have a five year survi val rate of 66%, but once metastatic disease has developed, there is no eff ective treatment. About 70% of patients with metastatic disease have bone i nvolvement, while lungs and liver are the other common targets. Bone metast ases cause severe pain, pathological fractures and hypercalcaemia and thus are a significant clinical problem. The development of new therapies for me tastatic breast carcinoma depends on a better understanding of the mechanis m of homing of the tumour cells to bone, liver and lungs and the factors re quired for their growth in these organs. Research on mechanisms of breast c ancer metastasis, particularly to bone, has relied on in vitro studies or o n tumour models in which the inoculation route is designed to promote deliv ery of tumour cells to a specific organ. Metastases in bone are achieved by inoculation into the right ventricle of the heart. To our knowledge there has been no report of a model of metastatic spread from the mammary gland t o distant sites which reliably includes bone. In this paper, we describe ou r recent development of a novel murine model of metastatic breast carcinoma . The new model is unique in that the pattern of metastatic spread closely resembles that observed in human breast cancer. In particular, these murine breast tumours metastasise to bone from the primary breast site and cause hypercalcaemia, characteristics not normally found in murine tumours, but c ommon in human disease. Furthermore, in a preliminary characterisation of t his model, we show that secretion of parathyroid hormone-related protein, a role for which has been implicated in breast cancer spread to bone, correl ates with metastasis to bone. This model therefore provides an excellent ex perimental system in which to investigate the factors that control metastat ic spread of breast cancer to specific sites, particularly bone. The specia l advantage of this system is that it involves the whole metastasis process , beginning from the primary site. Existing models consider mechanisms that pertain to growth of tumour once the site has been reached. An understandi ng of the regulation of these factors by potential therapeutic agents could lead to improvement in therapies designed to combat metastatic disease. Fo r the first time, this development will allow exploration of the molecular basis of site-specific metastasis of breast cancer to bone in a clinically relevant model.