Grant: Operating Grant

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths in North American women. The vast majority of breast cancer patients succumb to this disease due to the emergence of metastases, or the spread of cancer cells from the primary tumour to distant sites in the body. The liver is a prominent site for breast cancer metastasis and outcomes are poor for patients with unresectable hepatic metastases. We have shown that a protein, called Claudin-2, is enriched in liver metastatic lesions of breast cancer patients. We have demonstrated that Claudin-2 expression enhances the liver metastatic potential of breast cancer cells using pre-clinical mouse models. Thus, Claudin-2 is a potential target in the management of liver metastatic breast cancers. In this proposal, we will 1) determine how Claudin-2 expression is regulated in breast cancer cells, 2) develop agents to target Claudin-2 with the intent to reduce breast cancer-associated liver metastasis, 3) define the mechanisms engaged by Claudin-2 to promote liver metastasis and 4) develop pre-clinical transgenic mouse models of spontaneous breast cancer liver metastasis. Together, these studies have the potential to identify and generate new therapeutic agents that impair Claudin-2 expression or function that will be effective in reducing the formation of breast cancer liver metastases. In addition, we will uncover the molecular mechanisms through which Claudin-2 enhances the liver metastatic abilities of breast cancer cells.