Cellular resistance to chemotherapeutic agents is a major obstacle to cancer treatment. Therapy-induced overexpression of ATP-binding cassette (ABC) drug efflux pumps promotes resistance in many drug-treated cancers. While early studies focused on overexpression and activity of the P-glycoprotein (Pgp) pump, a structurally distinct group of ABC efflux pumps, known as the Multidrug Resistance Proteins (MRPs), have been gaining increasing attention as alternative sources of resistance. We have recently shown that MRP7 is distinct from other MRPs in conferring resistance to a wide variety of anticancer agents including taxanes, vinca alkaloids, epothilone B and nucleoside-based agents. However, little is known about the in vivo role of MRP7. In preliminary studies, we generated an Mrp7-/- knockout model, and established that these mice are sensitized to treatment with paclitaxel even though they are wild type for Pgp, thought to be the major taxane efflux pump. In a recent collaborative study we showed that in cultured cells, MRP7 activity is inhibited by lapatinib, a dual inhibitor of the ErbB1/ErbB2 tyrosine kinase receptors that is becoming a common agent in clinical management of breast cancer. Based on these data, we hypothesize Mrp7 expression and activity might be a hitherto unappreciated modulators of breast cancer resistance to drug treatment. To test this idea, we have developed two breast cancer models. First, we have crossed Mrp7-/- knockout mice to the MMTV- Polyoma Virus middle T antigen (PyVMT) mammary tumor model, derived cell lines from the mammary tumors, and begun analysis of drug resistance. We have also begun crossing Mrp7-/- knockout mice to the well- established MMTV-ErbB2/HER2/neu mouse model, considered the most physiological for human breast cancer, and will also derive cell lines from mammary tumors from this model. We propose two Aims to investigate the in vivo role of Mrp7, as well to determine the mechanism of MRP7-dependent chemoresistance in cancer cells. The proposed aims this proposal will address are: 1) To assess MRP7 as a resistance factor in breast cancer and 2) determine if lapatinib inhibits Mrp7 in vivo activity and further define the nature of this inhibition. Our ultimate goals are to determine if MRP7 expression can be used as a biomarker for treatment specifically, and if the knowledge of MRP7 status can be used to develop improved treatment strategies for breast cancer.
The identification of MRP7 as an in vivo chemoresistance factor for breast cancer would be completely novel and is relevant to public health. Our preliminary data indicate both intrinsic and drug-selected variance in levels of MRP7 expression, suggesting analysis and targeting of MRP7 has considerable potential to improve treatment of human breast cancer and this is directly relevant to NCI's mission of bringing novel therapies to cancer patients.
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