Detection, Prevalence, and Histopathological Correlation of Estrogen Receptor Alpha (ERα) Mutations – Y537N & D538G, in Luminal A & Luminal B Breast Cancer Patients

Abstract

Breast cancer (BC), a multifactorial malignancy with diverse clinical, histological, and molecular subgroups, predominantly expresses the estrogen receptor alpha gene (ERα), encoded by the ESR1 gene, in about 70% of cases. Endocrine therapy has become a cornerstone in managing ER+ BCs across all disease stages. However, intrinsic and acquired endocrine resistance to hormonal therapy remains a major challenge. Recent evidence suggests that point mutations in the ligand-binding domain (LBD) of the ESR1 gene, particularly the Y537N and D538G mutations, contribute to endocrine resistance. Our study aimed to evaluate the prevalence of ESR1 LBD mutations and their association with histopathological and clinicopathological parameters in ER+ BC patients of Pakistani origin. Biopsies and formalin-fixed paraffin-embedded (FFPE) tissue samples from 73 patients were analyzed, conducting manual DNA extraction followed by PCR amplification and gel electrophoresis to detect the Y537N and D538G mutations. Statistical analysis was then performed to assess the prevalence of these mutations and their relationship with various features. Results revealed a prevalence rate of 76.71% for the Y537N mutation and 13.69% for the D538G mutation. These mutations were more common in high-grade invasive ductal carcinomas. Furthermore, in silico studies indicated that these mutations were pathogenic and had deleterious effects on the respective proteins. Our findings underscore the importance of understanding the genomic landscape of ER+ BC and its implications for treatment resistance. Moving forward, this research lays the groundwork for exploring new therapeutic avenues in pre-clinical models that accurately mimic the complexity at genetic level of the patient tumors.