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Abstract

Breast cancer affects approximately one woman in twelve and kills more women than any other cancer. If detected early, patients have a five year survival rate of 66%, but once metastatic disease has developed, there is no effective treatment. About 70% of patients with metastatic disease have bone involvement, while lungs and liver are the other common targets. Bone metastases cause severe pain, pathological fractures and hypercalcaemia and thus are a significant clinical problem. The development of new therapies for metastatic breast carcinoma depends on a better understanding of the mechanism of homing of the tumour cells to bone, liver and lungs and the factors required for their growth in these organs. Research on mechanisms of breast cancer metastasis, particularly to bone, has relied on in vitro studies or on tumour models in which the inoculation route is designed to promote delivery 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 to distant sites which reliably includes bone. In this paper, we describe our 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 common in human disease. Furthermore, in a preliminary characterisation of this model, we show that secretion of parathyroid hormone-related protein, a role for which has been implicated in breast cancer spread to bone, correlates with metastasis to bone. This model therefore provides an excellent experimental system in which to investigate the factors that control metastatic spread of breast cancer to specific sites, particularly bone. The special 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 understanding of the regulation of these factors by potential therapeutic agents could lead to improvement in therapies designed to combat metastatic disease. For 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.

Hsp72 chaperone function is dispensable for protection against stress-induced apoptosis

“…The tumorigenic mouse fibroblast L929 cell line and the mouse mammary carcinoma 4T1.2 cell line (Lelekakis et al 1999) were maintained in Dulbecco's Modified Eagle's Medium and alpha minimal essential medium, respectively, supplemented with 10% fetal calf serum and 1% penicillinstreptomycin. Cultures were maintained at 37°C in a humidified 5% CO 2 atmosphere.…”

Caveolin-1 inhibits breast cancer growth and metastasis

“…We identified caveolin-1 in a microarray screen for genes involved in breast cancer progression using an orthotopic model of spontaneous breast cancer metastasis (Lelekakis et al, 1999). The model comprises cell lines that were derived from a spontaneous mammary carcinoma in a Balb/c/C3H mouse and exhibit different patterns of spontaneous metastasis following injection into the mammary fat pad (Aslakson and Miller, 1992;Lelekakis et al, 1999).…”

“…The model comprises cell lines that were derived from a spontaneous mammary carcinoma in a Balb/c/C3H mouse and exhibit different patterns of spontaneous metastasis following injection into the mammary fat pad (Aslakson and Miller, 1992;Lelekakis et al, 1999). 4T1.2 and 4T1.13 tumors are highly metastatic to lymph nodes, bone, lungs and other organs.…”

“…These lines provide a rare and valuable model that closely resembles the events that occur in metastatic breast cancer in humans, with spontaneous metastasis from the mammary gland to distal sites, including spine and femur. In contrast, tumors derived from the 66cl4 line show low levels of metastasis to lymph nodes and lung, while the 67NR line exhibits no metastatic capacity (Lelekakis et al, 1999;Eckhardt et al, submitted for publication).…”

Cyclin E in breast tumors is cleaved into its low molecular weight forms by calpain

“…Treatment of ZR75 cultures with calcium+A23187 recapitulated the formation of the calcium/calpain-induced LMW forms of cyclin E. Altered calcium homeostasis and/or inability of the endogenous calpain inhibitor to control the activity of high levels of the calpain small subunit may contribute to increased calpain activity in breast tumors, causing abundant levels of LMW cyclin E. Oncogene (2003Oncogene ( ) 22, 769-774. doi:10.1038 Keywords: cyclin E; calpain; breast cancer Numerous genetic abnormalities have been associated with breast cancer including activation or overexpression of oncogenes, and inactivation of tumor suppressor genes. In addition, aberrant expression and activity of cell cycle related genes have been observed in a variety of breast cancers (Ford et al, 1998;Steeg and Zhou, 1998;Lelekakis et al, 1999). Cyclin E, a regulatory subunit of Cdk2 that plays an important role in G 1 /S transition, is overexpressed and exists as low molecular weight (LMW) forms in breast cancer cells and tissues (Buckley et al, 1993;Keyomarsi and Pardee, 1993;Keyomarsi et al, 1995;Keyomarsi and Herliczek, 1997;Harwell et al, 2000).…”