Abstract A043: LRIG1: A novel molecular switch for overcoming endocrine resistance in estrogen-receptor positive breast cancer

Abstract Breast cancer (BC) is the most commonly diagnosed cancer among women worldwide. The majority of cases are hormone receptor-positive (HR+), making hormone receptors a key therapeutic target. However, over a third of initially hormone-sensitive tumors develop resistance to endocrine therapy, resulting in recurrent disease that is harder to treat and often requires combinatorial therapies. Notably, therapy-resistant tumors frequently acquire mutations in genes that activate growth factor signaling pathways, promoting uncontrolled cell cycle progression independent of external growth signals. One gene of growing interest is LRIG1 (Leucine-Rich Repeats and Immunoglobulin-like Domains 1), a bona fide tumor suppressor involved in regulating both hormone and growth factor receptor signaling. Dr. Jenkins-Lord’s previous work identified that LRIG1 is frequently hypermethylated and downregulated in aggressive BC, suggesting a strong inverse relationship with disease progression. LRIG1 encodes a transmembrane protein that antagonizes tumor growth by repressing receptor tyrosine kinases (RTKs), including EGFR and HER2-4. In a ligand-dependent or -independent manner, LRIG1 binds RTK ectodomains, recruiting c-CBL, an E3 ubiquitin ligase that tags RTKs for degradation. This mirrors the effect of neratinib, a tyrosine kinase inhibitor (TKI), by reducing downstream HER2 signaling. However, LRIG1 antagonizes multiple RTKs and may overcome resistance mechanisms commonly seen with small-molecule inhibitors. Thus, LRIG1 may function as a switch for treatment resistance, where silencing promotes resistance and activation restores drug sensitivity. Despite this, the mechanism regulating this switch remains poorly understood. Given its downregulation in BC, LRIG1 upregulation represents a potential therapeutic strategy to improve relapse-free survival. For preliminary analyses, Western blotting confirmed reduced LRIG1 protein in endocrine-resistant cells. We assessed LRIG1 levels and performed differential gene expression analysis comparing high- vs. low-LRIG1-expressing samples. Additionally, computational analysis of Gene Expression Omnibus (GEO) datasets from RTK-driven, therapy-resistant BC cell lines was conducted. Datasets with acquired HER2 and FGFR mutations linked to endocrine resistance showed distinct gene expression profiles in high-LRIG1 samples. Collectively, these studies aim to elucidate pathways by which LRIG1 modulates ER and RTK-driven resistance mechanisms in ER+ breast cancer. Citation Format: Kayla S. Ingram, Jaclyn Morgan, Brittany Jenkins-Lord. LRIG1: A novel molecular switch for overcoming endocrine resistance in estrogen-receptor positive breast cancer [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 A043.