Genetic Susceptibility to Cancer Chemotherapy in Human Breast Cancer

Abstract

Abstract : The treatment of breast cancer patients with chemotherapy is empirical. Even the most active drugs produce meaningful responses in <50% of patients. As a result, too many patients are needlessly exposed to highly toxic drugs and suffer the side effects without reaping the benefits. p53 is commonly mutated in human breast cancer (1). Recent studies demonstrate that p53 mutations also affect the sensitivity to cancer chemotherapeutic drugs (2-5). In studying the mechanism(s) underlying this observation, we found that increased expression of microtubule associated protein 4 (MAP4), which occurs when p53 is transcriptionally silent, is associated with increased sensitivity to paclitaxel and decreased sensitivity to vinca alkaloids (6). Using murine fibroblasts transfected with MAP4, we directly demonstrated that these changes in drug sensitivity were a consequence of overexpression of MAP4. Immunofluorescent staining of the microtubule network revealed that cells with increased MAP4 expression contained greater polymerized microtubules and bound more fluoresceinated paclitaxel than controls (6). Since MAP4 stabilizes polymerized microtubules (7, 8), overexpression of this gene provides a plausible mechanism to explain the sensitivity to microtubule-active drugs in the presence of mutant p53. The overall purpose of our present studies is to test the idea that overexpression of MAP4, as a consequence of functional loss of p53, can predict responsiveness to taxane and vinca alkaloid chemotherapy in human breast cancer. For these studies, we begin by analyzing a panel of breast cancer cell lines whose p53 status is known to determine whether or not there is a correlation between p53 transcriptional activity and expression of MAP4.