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ESTROGEN RECEPTOR AND ENDOCRINE RESISTANCE

About the Project

The estrogen receptor (ER; ESR1) pathway plays a pivotal role in breast cancer development and progression, and approx 70% of breast cancer cases are ER positive. Targeting ER has been one of the most successful targeted therapies in oncology. However, the effectiveness of endocrine therapy is limited by high rates of de novo and acquired resistance in clinic. Thus, it is crucial to understand the molecular mechanisms causing endocrine resistance.  Our currently ongoing projects are focused on functional analysis of genetic variants in ER, its binding sites as well as its co-regulators.

A) Determine the role of ESR1 mutations in regulating endocrine resistance and driving metastasis. Hotspot somatic ESR1 mutations can be detected in  metastatic tumor samples and cell-free circulating DNA in 20-40% of patients with endocrine resistant tumors. We have generated genomic edited cell models for the most frequent ESR1 mutations (Y537S and D538G ) in multiple breast cancer cell lines, and are now utilizing state-of-the-art technologies to decipher how these mutations drive endocrine resistance and metastasis in breast cancer.

B) Explore the alternative functions of DNA sequence variants (DSVs, ie germline polymorphisms and somatic mutations) in ER binding sites, and in ER coregulators. In this project, we are trying to understand how DSVs in ER binding sites influence the recruitment of ER and ER co-regulators, and the subsequent effects on hormone responses. We are also studying DSVs in the nuclear receptor co-activator SRC1/NCOA1.