Grant: Project Grant

Breast cancer is the most frequently diagnosed cancer and second leading cause of cancer death among Canadian women. Estrogens contribute to breast tumorigenesis by acting via a specific effector, estrogen receptor alpha (ER), present in 2/3 breast tumors. Inhibition of estrogenic action is achieved for therapeutic purpose via different drugs that have distinct mechanisms of action, collectively known as hormonal therapies. However, resistance occurs in 30-50% of breast cancer patients treated with hormonal therapies. The mechanisms of action of antiestrogens, a class of drugs frequently used for both first and second line hormonal treatment of ER+ breast cancer, are still not fully understood, preventing their optimal use in patients relapsing after hormonal therapies. The Mader lab has uncovered novel mechanisms of action for antiestrogens that explain the spectrum of clinical profiles displayed by this class of molecules, and has characterized the impact of different antiestrogens in models of resistance to hormonal treatments due to different genetic changes in the estrogen receptor. The current application will further characterize aspects of the mechanisms of action of antiestrogens that remain poorly understood, such as the proteins that cooperate with the estrogen receptor to lead to resistance to these agents. The team will also investigate novel therapeutic combinations that would increase response in progressing patients by suppressing estrogen signalling more efficiently.