Abstract A046: LRIG1 as a molecular driver of breast cancer disparities: Evidence from genetic and functional studies

Abstract Background: The aggressive breast tumor biology experienced by African American (AA) women is rooted in both genetic and environmental causes and we are interested in investigating the molecular drivers influencing this complex health disparities problem. We previously identified significant downregulation and hypomethylation of the tumor suppressor LRIG1 in the breast tumor tissues from AA women living in socioeconomically deprived neighborhoods. LRIG1 encodes a transmembrane protein that downregulates growth receptor signaling, with reduced expression linked to poorer survival outcomes. This project aims to: (1) evaluate associations between LRIG1 variants and molecular, clinical, and sociodemographic data in a diverse BC cohort, and (2) investigate LRIG1’s functional role in diverse BC cell line models. We hypothesize that (1) pathogenic LRIG1 variants are more strongly associated with BC susceptibility and adverse clinical outcomes in AA women, and (2) reintroduction of LRIG1 to LRIG1-knockdown cells will restore a less proliferative, LRIG1-competent phenotype. Methods: We genotyped LRIG1 SNPs (rs2306272, rs1403626) in 419 breast tissue samples (cases: AA=135, EA=81; controls: AA=115, EA=88) using PCR and fluorescent detection. We analyzed associations between SNPs and race, clinical features, and BC risk factors. In parallel, we performed proliferation assays in T47D ER+ cells after transient LRIG1 knockdown (siLRIG1), with and without recombinant LRIG1 (rLRIG1) supplementation. Results: Minor allele frequencies for both SNPs aligned with known population data. Significant associations were observed between rs2306272 and self-reported race (p<0.0001), family history of BC (p=0.0037), and tumor grade (p=0.0768), and between rs1403626 and race (p<0.0001). Functionally, rLRIG1 reintroduction in siLRIG1 T47D cells significantly reduced cell proliferation compared to siLRIG1 alone. Conclusions and Future Directions: This is the first report linking rs2306272 with race and clinical BC characteristics. Ongoing work includes analyzing SNP-methylation associations to identify ancestry-linked epigenetic regulation of LRIG1. Our functional data supports LRIG1 as a suppressor of BC cell proliferation. We will next generate stable LRIG1-knockdown and -overexpression cell lines to further elucidate its role in diverse BC models. Citation Format: Angel H. Pajimola, Amber Yu, Brittany Jenkins-Lord. LRIG1 as a molecular driver of breast cancer disparities: Evidence from genetic and functional studies [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr A046.