Grant: Project Grant

Breast cancer is the most frequently diagnosed cancer and second leading cause of cancer death among Canadian women. Estrogen signaling contributes to mammary tumorigenesis and is mediated by estrogen receptor alpha (ER), a major therapeutic target in ~2/3 of breast tumors. Drugs used in the clinic to inhibit this protein include antiestrogens, which bind to this protein and inactivate it. However, some antiestrogens such as tamoxifen still enable partial activity of ER, while others such as fulvestrant are more complete inhibitors ("pure antiestrogens"). While the efficacy of fulvestrant in the clinic is limited by poor oral delivery, it is important for the design, testing and use of novel pure antiestrogens to understand the mechanisms of action specific to this type of drugs. Our research has shown that fulvestrant uniquely induces efficient modification of ER by serial addition of small proteins (SUMO proteins), which contributes to inactivating the receptor in model cell lines. We have characterized the chemical structures of antiestrogens and the regions of ER important for these modifications to take place. We also observed that some mutations of ER associated with resistance to hormonal therapies prevent partially or totally this mechanism of repression. We wish now to test the hypothesis that modification of ER by SUMO proteins is important for the optimal suppression of tumor growth. To this end, we will systematically characterize the mechanisms and impact of SUMO addition on ER functional properties, and test whether this results in an improved capacity to suppress tumor progression in pre-clinical models. These studies should (i) clarify the mechanisms of action of pure antiestrogens (ii) help guide their use in the clinic (iii) facilitate the design and testing of novel pure antiestrogens for the treatment of advanced ER+ breast tumors, a major cause of mortality in breast cancer patients.