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    Research Grants Awarded

    In Vitro and In Vivo Models for Chemoresistance

    Study Section:
    Tumor Cell Biology IV

    Scientific Abstract:
    Background. Resistance to chemotherapy is a major predicament in the treatment of breast cancer. One of the mechanisms underlying tumor resistance is via local production of anti-apoptotic Bcl-2 proteins. Two lines of evidence suggest that prolactin (PRL), a hormone produced by both the pituitary and the breast, reduces the efficacy of anticancer drugs by activating endogenous mechanisms that oppose cell death. One, PRL-overexpressing breast cancer cells implanted in nude mice generated rapidly growing tumors with increased Bcl-2 expression. Two, PRL at very low doses protects cultured breast cancer cells from death induced by taxol and cisplatin. Hypothesis . Both circulating and breast-derived PRL reduce the efficacy of anticancer drugs. To validate this concept, we will establish well-defined culture conditions and develop unique animal models. Specific aims. 1) determine protection by PRL against drug-induced cell death in vitro . 2) use cells encapsulated in hollow fibers to rapidly screen anticancer drugs in PRL -/- and PRL +/+ transgenic mice. 3) compare tumor growth and sensitivity to anticancer drugs in immune-compromised and PRL-deficient (Rag2/PRL -/- ) mice implanted with PRL-producing breast cancer cells. Study design. 1) incubate MDA-MB-468, MDA-MB-231 and T47D cells with taxol, cisplatin and vinblastine in the presence or absence of PRL and determine cell viability. 2) PRL +/+ and PRL -/- mice implanted with encapsulated cells are treated with anticancer drugs. Fibers are retrieved within two weeks and analyzed for cell viability. 3) Rag2/PRL -/- mice are inoculated with breast cancer cells that express tetracycline-inducible PRL and exposed to doxycycline and anticancer drugs. The capacity of breast-produced PRL to stimulate tumor growth and resist drug-induced tumor shrinkage is evaluated. Potential outcomes. We offer a plausible explanation for failure of chemotherapy in those patients with elevated serum PRL levels or overexpression of PRL receptors (PRLR) in their tumors. Serum PRL can be safely reduced by bromocriptine. Analysis of the PRLR in tumor biopsies should be predictive of the success of chemotherapy. Such knowledge should lead to optimization of drug dosages on an individual basis. Treatments aimed at blocking actions of PRL on tumor cells are presently under development. Ultimately, rational management of PRL production and actions in patients should increase the efficacy of chemotherapy in halting the disease.

    Lay Abstract:
    Background. The fundamental goal of chemotherapy is the elimination of cancer cells. Anticancer drugs are effective in treating early-stage and metastatic breast cancer but tumor resistance remains a major obstacle. One of the mechanisms responsible for chemoresistance is increased production of survival proteins which antagonize the killing of cancer cells by chemotherapeutic agents. Prolactin, a hormone made by both the pituitary gland and the breast, protects cultured breast cancer cells from death induced by taxol and cisplatin. In mice, prolactin-producing breast cancer cells generate rapidly growing tumors with increased amounts of survival proteins. This suggests that prolactin activates internal cellular systems that oppose chemotherapeutic agents. Hypothesis . Prolactin confers resistance against selected anticancer drugs. To validate this premise, we will develop unique cell culture systems and animal models. Specific aims. 1) analyze the capacity of prolactin to prevent cell-killing by anticancer drugs in cultured breast cancer cells. 2) validate a method for cell implantation in mice without being rejected. 3) compare tumor growth and sensitivity to anticancer drugs in mice with normal serum prolactin levels and in those with genetically-deleted prolactin. Study design. 1) compare drug-induced killing of breast cancer cells incubated with or without prolactin. 2) implant cells, protected from rejection by enclosure in hollow fibers, in prolactin-negative and prolactin-positive mice. Use these for rapid screening of anticancer drugs that reduce cell viability. 3) implant prolactin-producing breast cancer cells in mice that are both prolactin-negative and immune-deficient. Use these to analyze the tumor shrinking effects of anticancer drugs. Potential outcomes. Failure of chemotherapy in some patients could be due to their high serum prolactin levels or to increased activity of the prolactin receptor in their tumors. Serum prolactin can be safely reduced by orally administered pills. Analysis of prolactin receptors in tumor biopsies should be predictive of the success of chemotherapy, enabling adjustment of drug dosages on an individual basis. Several treatments capable of blocking prolactin actions on tumors are currently under development. Ultimately, rational management of prolactin release and actions in breast cancer patients should increase the success of chemotherapy in halting the disease.