In the course of cancer chemotherapy, an initial remission may be followed by drug-resistant relapse. Drug resistant cell populations can arise from selective pressure of chemotherapy, combined with mutations or epigenetic changes that confer a selective growth advantage to drug-resistant tumor cells. Recently, it has been found that cancer cells shed large numbers of nanometer-sized, cell surface-derived particles both in vivo and in vitro. We hypothesize that these particles represent an anticancer drug efflux mechanism, involved in drug resistance. If confirmed, understanding this mechanism would help design anticancer drugs with increased efficacy, and would facilitate development of novel pharmacological agents for blocking drug resistance. In support of this hypothesis, preliminary evidence obtained in my laboratory indicates that expression of vesicle shedding-associated genes correlates with multidrug resistance. Statistical analyses of gene expression profiles in relation to chemosensitivity profiles spanning human derived cancer cell lines from different tissues indicate that vesicle shedding associated genes predict drug resistance profiles. Pulse-chase experiments with doxorubicin and other small, fluorescent molecules confirm that vesicles shed from the surface of cancer cells can mediate drug expulsion. Here, we propose to perform a pilot study of the contribution of vesicle-mediated drug expulsion to total anticancer drug efflux and resistance.
The first aim of this study will be to measure expulsion of drug in shed vesicles, using several different radiolabeled drugs as tracers, and relate drug expulsion to multidrug resistance across various breast tumor-derived cell lines. A second objective is to detect the presence of shed vesicles -or shed vesicle-associated antigens- in nipple aspirates and ductal lavage fluid obtained from breast cancer patients. Bilateral nipple aspirates and ductal lavage samples obtained prior to mastectomy will be analyzed for the presence of shed vesicles or shed vesicle-associated antigens using microscopic, biochemical and biophysical techniques. Establishing the presence of shed vesicles specifically in cancerous breast fluids would enable future studies of the role of vesicle shedding as a prognostic marker of drug resistance and cancer progression, and would constitute evidence for the physiological relevance of the shedding mechanism. ? ? ?
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