Investigating the genetic and molecular signatures of resistant breast cancer cells to chemotherapy

Breast cancer is considered the most prevalent type of cancer in Omani females with an increased incidence rate. Advanced Breast cancer patients are usually treated with neoadjuvant chemotherapy followed by surgery. Response to treatment varies among patients some show complete pathological and clinical response however others they don?t respond and finally they relapse with aggressive disease. In this proposal we will be studying the different mechanisms of resistance to chemotherapy in an in vitro model. Three breast cancer cell lines will be used with different molecular subtypes to represent three known breast cancer subtypes, Luminal A (MCF7), Luminal B (BT-474) and Triple Negative (MDA-MB-231). The cells will be treated in monolayer as well as three dimensional cell culture conditions with different types of chemotherapies for consecutive cycles which represent the clinical cycles and therapies used to treat BC patients. The formed resistant cells will be propagated and the mechanism of resistance will be studied in details by checking the gene expression of breast cancer resistant protein (BCRP) and the multi-drug resistant protein (MRP) to confirm the established resistance. Once the cells become resistant the transcriptome of each of the cell lines will be sequenced to check out which genes were up regulated or down regulated and compare the genotype with the cellular responses such as cell proliferation, colony formation ability, spheroid formation in 3 D cultures, and their ability to migrate and invade. Finally, knowing the genes associated with the resistance will lead to the design of a targeted therapy for those patients who don?t respond to treatment and will show the difference among the different subtypes of breast cancer and fine tune the choice of treatment in a more specified and personalized manner.