Preclinical Models Of Metastatic Disease

Breast cancer is a disease that continues to take the life of approximately 40,000 men and women in the United States each year [1]. Tumor drug resistance represents a major problem for the treatment of many breast cancer patients. The mechanisms underlying such resistance remain to be elucidated, and one approach to study this issue involves the development of tumor drug-resistant breast cancer models in mice. HER-2 positive breast cancer is considered to be one of the most aggressive subtypes of breast cancer and has become a major target for treatment. HER-2 status is a routinely checked marker for breast cancer due to as many as 1/5 of patients overexpressing this gene, thus making it an ideal model to approach drug resistance in tumors. In this project, two human breast cancer models, derived from the HER-2 positive BT747 and MDA-MB-361 cell lines, will be characterized. Parental and drug sensitive populations were studied, which included the evaluation of the levels of protein expression of components of the HER-2 signaling pathway. A second approach involved intracardiac injection of tumor cells in mice to generate widespread metastases, and the subsequent evaluation of relative drug resistance to chemotherapy in metastases to different organs. Lastly, intracranial injection of cancer cells employed to address the increasing incidence of brain metastasis in breast cancer patients. My dissertation aims to uncover mechanisms by which cancer cells develop drug resistance, developing models of late-stage breast cancer and the combination of these models with metronomic chemotherapies