Amy H. Bouton, PhD
Protein tyrosine kinases in the regulation of growth control and pathogenesis
The Bouton research group has been studying molecular mechanisms by which breast cancer cells become resistant to the growth-inhibitory effects of antiestrogens. This is a significant problem in breast cancer treatment, since as many as 50% of breast tumors never respond to antiestrogen therapy (intrinsic resistance), and the majority of tumors that initially respond acquire resistance to these drugs over time (acquired resistance). Their work in this area is focused on understanding how overexpression of two proteins, the adapter molecule Cas and one of its binding partners AND-34, confer resistance to antiestrogens such as tamoxifen. Interestingly, a subset of human breast tumors that were shown to express abnormally high levels of Cas were also found to be significantly less likely to respond to first-line tamoxifen therapy, despite the fact that they were estrogen receptor (ER)-positive. They have begun to investigate the molecular mechanisms that contribute to Cas-dependent tamoxifen resistance. They have found that the transcriptional activity of the ER is appropriately regulated by estradiol and tamoxifen in Cas- or AND-34 overexpressing breast cancer cells. This suggests that Cas overexpression promotes tamoxifen resistance through a pathway that is independent of the transcriptional functions of the ER. Their data indicate that this pathway may involve the establishment of a molecular complex between Cas and the protein tyrosine kinase c-Src. Cas binding prevents the adoption of an autoinhibitory conformation by c-Src, resulting in a more active kinase. Preliminary evidence suggests that two c-Src substrates, tyrosine residue 845 on the epidermal growth factor receptor (EGFR) and the transcription factor Stat5b, may synergize with Cas to promote tamoxifen resistance. They are currently investigating the role played by these and other c-Src substrates in promoting antiestrogen resistance through Cas. These studies are being performed in collaboration with several other Cancer Center investigators, most notably Drs. Sarah Parsons, Margaret Shupnik, and Corinne Silva. Through this work, the lab hopes to be able to 1) better predict whether a particular tumor is likely to fail antiestrogen therapy so that other treatment approaches can be initiated more quickly; and 2) render previously resistant tumors sensitive to tamoxifen treatment by blocking Cas-, AND-34- and/or c-Src-dependent signaling pathways.