Targeting Mechanisms of Endocrine Resistance in Breast Cancer

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Project Summary/Abstract Endocrine therapies that inhibit estrogen receptor (ER) signaling are the mainstay of the systemic treatment of ER+ breast cancers. These therapies consist of approaches to reduce estrogen levels including luteinizing hormone-releasing hormone (LHRH) agonists in premenopausal women and aromatase inhibitors (AI) in postmenopausal women, and direct ER antagonists such as tamoxifen and fulvestrant. In the advanced disease setting, however, endocrine therapy-resistant cancers almost invariably emerge and are the major cause of breast cancer deaths. Multiple genetic and epigenetic mechanisms have been proposed to explain the emergence of endocrine therapy resistance. Several groups including our own have characterized mutations in the ER gene (ESR1) itself as a mechanism of resistance in approximately 20-30% of cases. We have developed cell line and patient-derived xenograft (PDX) models of endocrine therapy-resistant ER+ breast cancer driven by these ESR1 mutations and have found that these mutations exhibit both ligand-independent functions that mimic estradiol-bound wild-type ER as well as allele-specific neomorphic properties that confer on ER novel signaling functions that promote a pro-metastatic EMT-like phenotype. In addition, using genome-wide CRISPR screens, we have identified genes essential for the growth of ER+ breast cancers. Importantly, we have also identified genes whose loss confers endocrine therapy resistance in the setting of the wild-type ER, including NF1, TSC1/2, PTEN and CSK. In these studies, we have found that loss of CSK leads to activation of SRC-family kinases (SFK), thereby promoting estrogen-independent growth and a pro-metastatic cancer cell phenotype. Notably, expression of CSK is regulated by estrogen through binding of ER directly to a transcriptional enhancer in the CSK gene. This reveals the existence of an estrogen-induced negative feedback loop that constrains the growth of ER+ tumors thereby limiting the efficacy of current therapies that target ER. The existence of this feedback loop suggests the provocative hypothesis that current endocrine therapies may themselves promote a pro- metastatic phenotype. Consistent with the overarching theme of this program to define new therapeutic vulnerabilities, we will study how genetic and epigenetic heterogeneity impact the development of resistance to endocrine therapy. Success of this project will allow the development integrative models of the mechanisms of endocrine therapy resistance that include the effect of tumor heterogeneity that can be used to predict effective new therapeutic targets and will allow the investigation of the link between endocrine therapy resistance, endocrine therapy and metastasis.