Study of Estrogen Receptor-Mediated PGx-eQTLs Identifies Genetic Determinants of Breast Cancer Endocrine Therapy Response

Endocrine therapy remains the cornerstone of treatment for estrogen receptor alpha (ERα)-positive breast cancer, yet the relationship between individual genetic background and molecular response to ERα-targeted therapy remains incompletely understood. Using a well-characterized panel of lymphoblastoid cell lines (LCLs), we performed genome-wide pharmacogenomic expression quantitative trait locus (PGx-eQTL) analysis to identify estradiol (E2)- and tamoxifen (TAM)-induced SNP-gene pairs. PGx-eQTL signals were integrated with previously published breast cancer genome-wide association study datasets to examine their association with clinically relevant breast cancer phenotypes. We identified two ER-mediated PGx-eQTL SNP-gene pairs associated with breast cancer prognosis post-treatment with E2 or TAM. Notable loci included E2-regulated MRPL15 and TAM-regulated SYCP3, which have effects in a genotype-dependent manner, with genotype-dependent survival outcomes, from worse to better relapse-free survival. Similar endocrine-therapy effects on patient survival and breast cancer risk were observed in SIK2, post TAM-treatment, and in LSM4 with E2-treatment. Moreover, qRT-PCR validation in an independent LCL panel confirmed the genotype-specificity of these signals. Overall, we identified ER-mediated PGx-eQTL SNP-gene pairs which represent potential pharmacogenomic tools for identifying patients likely to benefit from ERα-targeted endocrine therapy, offering a foundation for more genotype-informed individualized treatment decisions in breast cancer.