Breast cancer is the most common form of cancer affecting a large population of women worldwide. Chemotherapy has been the most effective form of treatment against breast cancer. Despite advances in early diagnosis and understanding of the molecular bases of breast cancer biology, recurrence of the disease is seen in nearly 30% of patients with early-stage breast cancer. Treatment in majority of these patients is highly impeded by resistance of cancer cells to chemotherapeutic drugs. This project aims to structurally determine BCRP a protein that is responsible for drug resistance in several types of cancer, including breast and brain cancer.
The human Breast Cancer Resistance Protein (BCRP) is a drug efflux pump responsible for conferring drug resistance to many chemotherapeutic agents used for breast cancer treatment. Overexpression of BCRP is associated with high levels of resistance to a variety of anticancer agents used in breast cancer treatment, including anthracyclines, mitoxantrone, and the camptothecins. In addition, BCRP actively transports highly diverse range of non-chemotherapeutic drugs as well as non-therapeutic compounds. In addition to playing an important role in conferring drug resistance, high levels of BCRP expression in various tissues implicate its importance in normal physiology. These include stem cells from a variety of tissues indicating a role in protection from xenobiotics, as well as in organs important for absorption (the small intestine), distribution (blood–brain, blood–testis and maternal–fetal barriers) and elimination (liver and kidney) of drugs. Determining its molecular architecture will therefore provide an understanding of its mechanism. We propose to discover, by structural means and biochemical studies, the binding site and key residues involved in drug interaction in BCRP, which in turn will facilitate designing of highly selective inhibitors that can restore drug sensitivity in cancer cells.