Estrogen Receptor Alpha and ESR1 Mutations in Breast Cancer

Adv Exp Med Biol. 2022;1390:171-194. doi: 10.1007/978-3-031-11836-4_10.ABSTRACTThe estrogen receptor alpha (ERα) is a nuclear transcription factor that is expressed in more than 70% of all breast cancers. Key genes involved in proliferation and tumor progression are transcriptionally regulated by ERα making it an important therapeutic target. Indeed, the first class of targeted treatments in cancer are endocrine treatments that target ERα either by competitive inhibition, reduced ligand production or receptor degradation. Despite the efficacy of these drugs, resistance to endocrine treatment remains a key clinical challenge. Only about 50% of patients treated with endocrine treatment in early-stage disease will benefit from adjuvant endocrine treatment and nearly all patients treated in the metastatic setting will develop disease progression while on endocrine treatment. Multiple mechanisms of resistance to endocrine treatment have been identified in pre-clinical models and clinical samples. These include both intrinsic (de novo) mechanisms and adaptive, acquired mechanisms. Over the past few years, gain-of-function missense mutations of ESR1, the gene encoding ERα, have been unveiled and identified as the most common genomic mechanism of acquired resistance to endocrine treatments. These mutations are clustered in a "hot spot" region within the ligand binding domain and engender constitutive, ligand-independent activity. Clinical studies evaluating these ESR1 mutations i...
Source: Advances in Experimental Medicine and Biology - Category: Research Authors: Source Type: research