Genetic Susceptibility to Cancer Chemotherapy in Human Breast Cancer

摘要

Previously CINJ (Cancer Institute of New Jersey) showed that MAP4, MRP and stathinin are regulated by the tumor suppressor protein, p53. These proteins play roles in microtubule dynamics as well as transport of chemotherapeutic drugs. In the past year CINJ focused on stathmin's role in cell cycle control and drug sensitivity. Stathmin destabilizes microtubule polymers through interactions with tubulin heterodimers. Since several chemotherapeutic agents used in the treatment of breast cancer target microtubule components, stathmin may play a role in determining sensitivity to these drugs. This is particularly important since stathmin is often upregulated in breast cancer. CINJ's current studies show that overexpression of stathmin leads to decreased microtubule polymerization and decreased sensitivity to both vinblastine and paclitaxel. This was intriguing given the concurrent increased cellular association of vinblastine. Cell lines overexpressing stathmin were more likely to enter G2 but less likely to enter mitosis as measured by mitotic figure counts. These data suggest that stathmin-mediated arrest may block chemotherapeutic drugs that are active in mitotic cells. These studies also suggest that mutant p53 breast cancer exhibiting high levels of stathmin may not be fully responsive to antimicrotubule agents in the face of an intact G2/M check point.