Brk and mTOR signalling: implications for Taxol resistance

One of the major causes of death amongst breast cancer patients is due to the development of distal metastases and the acquisition of resistance to chemotherapeutic agents. There is a scientific and clinical need to understand the alterations in cellular signalling pathways that could contribute to chemotherapeutic resistance in breast cancer.

Our preliminary data implicate both that Brk expression and mTOR signalling are up-regulated in resistance to Taxol, a chemotherapeutic drug that is widely used in treating breast cancer. This project seeks to investigate the involvement of Brk, a kinase overexpressed in up to 86% of breast cancers, in regulating mTOR signalling in the development of Taxol resistance. You will examine the gene expression of mTOR components by real-time Q-PCR in Brk-suppressed and Brk-overexpressing breast cancer cells. Relative phosphorylation levels will also be determined using phospho-specific antibody arrays. To determine whether mTOR, is a Brk substrate, we will immunoprecipitate Brk and western blot for members of the mTOR pathway. We will also examine whether Brk influences the effects of mTOR inhibitors and whether combinations of Brk and mTOR inhibitors alter sensitivity to Taxol in Taxol-resistant cells