Abstract 777: Notch signaling dependent chemoresistance in racial disparity in ER+ breast cancer

Abstract

Abstract Breast cancer (BCa) is the leading cause of cancer related death in women worldwide. The most common BCa subtype is the Estrogen/Progesterone receptor (ER+/PR+) luminal subtype, comprising up to 75% of all newly diagnosed BCa. Although these patients show initial benefit with chemotherapy and endocrine therapy, however, 40-50% of them eventually don’t respond to treatment due to resistance. Thus, the need for additional targeted therapies for this large subset of ER+ BCa patients is critical. Based on recent studies, it is observed that Afro-American (AA) patients experience substantially higher BCa mortality (40% more) than White American (WA) women in ER+ breast cancer. Unfortunately, the cause behind this difference in mortality in AA patients is not well understood. Notch signaling is a highly conserved intercellular communication mechanism critical for many cellular processes and is composed of several receptors and ligands. Recent data show that Notch receptors are overexpressed in hormone treatment refractory ER− patients of (Afro-American) AA origin, hinting connection of Notch signaling to racial disparity in breast cancer. Notch signaling is also identified in several metabolic disorders involving fatty acids and other lipids. However, function of Notch signaling in context of chemoresistance in AA ER+ breast cancer is still unknown. Using single cell sequencing, we found that chemo-resistant AA ER+ breast cancer patient samples have a distinct Notch signature enriched subpopulations in tumor cells, which was missing in WA patients. Notch signaling happens through juxtacrine signaling of ligand/receptor signaling. Further analysis in tumor microenvironment shows lipid enriched tumor associated macrophages, which are Notch dependent, suggesting potential crosstalk between lipid heavy tumor-macrophages and tumor cells, which may drive the chemoresistance in AA patients. Further analysis using patient derived explants, an attractive new tool for drug efficacy testing in ex vivo, we found that chemotherapy itself increases Notch signaling in the tumors. Ongoing studies involving scRNAseq, untargeted lipidomics and chemo-resistant PDE will delineate the precise mechanism of action between tumor cells and tumor associated lipid heavy macrophages in context of Notch signaling in chemo-resistant AA ER+ breast cancer. Citation Format: Shailesh Singh, Megha Das, Rumela Chakrabarti. Notch signaling dependent chemoresistance in racial disparity in ER+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 777.