Abstract C119: Exploring the functional role of LRIG1 and WWOX tumor suppressors in breast cancer disparities

Abstract Breast cancer is the most commonly diagnosed cancer among women in the US. Despite a lower rate of breast cancer incidence, Black women in the US suffer higher rates of mortality compared to White women. This disparity poses a major clinical issue for Black women in the US, and we are particularly interested in understanding how molecular and environmental mechanisms may be contributing to these disproportionate outcomes. Our previous study found that in a cohort of women from Baltimore, Maryland (110 Black, 75 White), higher neighborhood deprivation was associated with decreased gene body methylation and gene expression of two tumor suppressor genes, LRIG1 and WWOX. These findings were unique to the tumor, which potentially points to ancestry-specific somatic mutations that may impact gene and protein expression for LRIG1 and WWOX. The goal of this project is to determine gene and protein differences in LRIG1 and WWOX by population group in women with and without breast cancer as it relates to neighborhood-level socioeconomic deprivation. We hypothesize that LRIG1 and WWOX exhibit decreased gene and protein expression in Black women compared to White women. Using the same diverse cohort from Baltimore, Maryland, we identified and conducted DNA genotyping on clinically relevant mutations of LRIG1 and WWOX using amplification by PCR and detection by fluorescent reporters. We found that the genotype frequencies in two single nucleotide polymorphisms (SNPs) for LRIG1, rs1403626 (P=6.3e-1) and rs2306272 (P=0.005967), differ significantly between population groups in these breast tissue samples, an interesting finding that matches our previous predictions. We also identified a dose-dependent relationship between LRIG1 gene expression and rs1403626 SNP genotypes. Additional patient genotyping will be conducted to determine relationships between LRIG1 and WWOX SNPs, differences in DNA methylation, and correlations with neighborhood deprivation measures. To interrogate the impact on protein expression, we will construct LRIG1 and WWOX knockdown mutants in estrogen receptor (ER)-positive and ER-negative commercially available breast cancer cell lines derived from Black and White patients, and determine the functional consequences of LRIG1 and WWOX loss by immunofluorescence and western blot, including how this may differ by population group. These studies will give us a better understanding of how the expression of tumor suppressor genes may contribute to the higher susceptibility of Black women developing more aggressive breast tumors. Citation Format: Angel H. Pajimola, Brittany Jenkins-Lord. Exploring the functional role of LRIG1 and WWOX tumor suppressors in breast cancer disparities [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C119.