Grant: Project Grant

Breast cancer is a prevalent world-wide disease but its manifestations are heterogeneous, necessitating treatment regimen adapted to the main tumor subtypes currently identified. Two thirds of tumors overexpress the estrogen receptor alpha (ER) compared to normal tissues and are candidates for targeted treatments that block estrogen signaling. These tumors are associated with the best prognosis. Estrogen receptor-negative tumors on the other hand are not sensitive to these treatments and, for a significant proportion of them, can be treated only with chemotherapy. Further, ER-positive tumors can become resistant during tumor progression. Thus, understanding why some tumors gain or lose expression and/or activity of this important therapeutic target is crucial to improving the appropriate classification and treatment of this disease. To address this question, the applicants have initiated large-scale screens in breast cancer cell lines that express ER. Through suppression of expression of each individual gene in the genome, they have identified candidate proteins that are thought to modulate the expression and/or activity of ER using a surrogate assay that measures the activity of this protein. In this application, they will use a recent and sensitive technology for modulation of gene expression called CRISPR-Cas9 to validate current candidates and identify new ones. In addition, candidate ER regulators identified in current and future screens will be characterized for their capacity to modulate ER expression and/or activity. Finally, whether defects in these ER regulators arise during breast tumorigenesis will be investigated using archived breast tumor samples, and the impact of these proteins on the tumorigenic properties of breast cancer cells and their response to ER-targeted treatments will be investigated in cell line and animal models.