RE-SENSITIZING ER-ALPHA MUTANT BREAST CANCER CELLS TO HORMONAL THERAPY

The majority of breast cancer cases are estrogen receptor (ER?)-positive. While hormonal therapyimproves clinical outcomes for about half of patients with ER?-positive breast cancer, de novo or acquiredresistance represents a significant clinical challenge. Among several underlying mechanisms, hot-spot pointmutants of ER? are known to confer therapeutic resistance due to their estrogen-independent transcriptionalactivity. Thus, mitigating aberrant transcription activity of these ER? mutants holds promise for overcomingtherapeutic resistance in treatment of ER?-positive breast cancer. As the second member of the ER family,ER? is capable of interfering with ER? activity through heterodimerization and/or competing for commonchromatin binding sites. This ER?-interfering function of ER? could be utilized to overcome the activity oftherapeutically resistant ER? mutants. However, clinical feasibility of this approach is vastly under-explored, aslittle is known about how ER?-interfering activity of ER? is mobilized. Our preliminary work discovered a functionally important phosphotyrosine switch in ER?. Specifically,we found that unphosphorylated ER? is particularly potent in heterodimerization and functional interferencewith ER?. We therefore hypothesize that unphosphorylated ER? in ER?-positive breast cancer can helpovercome ER? mutant-mediated therapeutic resistance. We further envision that pharmacological agentsthat fine-tune the phosphotyrosine status of ER? could be clinically useful in stimulating its ER?-interferingactivity. We will test this novel hypothesis through two Specific Aims. First, we will use in vitro and patient-derived xenograft models to determine the impact of ER? phosphorylation status on ER?-mediated therapeuticresistance. Second, we will use molecular and pharmacological tools to elucidate the mechanism by whichER? phosphorylation status regulates the ER?/? crosstalk. The concept of overcoming therapeutic resistance by rallying a particular form of ER? represents anovel concept. Furthermore, because the inhibitor of the upstream kinase for the phosphotyrosine switch isclinically available and ER?-specific agonists are well tolerated in humans, our work provides multipledruggable targets for fine-tuning ER? activities and imminent translatability for treating ER?-positive breastcancer. Our proposed study promises both conceptual and translational advances in understanding of how toovercome therapeutic resistance to hormonal therapy, a pressing clinical challenge in breast cancer treatment.