Abstract C119: Characterizing FOXC1 dysregulation in triple-negative breast cancer to advance precision therapies and reduce cancer health disparities

Abstract

Breast cancer is the most common cancer in women and the second leading cause of cancer death in the United States. Breast cancer has multiple subtypes defined by the expression of the estrogen receptor (ESR1), progesterone receptor (PGR), and human epidermal growth factor receptor 2 (HER2). Among breast cancer subtypes, the basal-like subtype frequently overlaps with triple-negative breast cancer (TNBC; ESR1−, PGR−, HER2−) and is disproportionately more common in certain populations, with the strongest association being among women of African ancestry. TNBC presents a significant therapeutic challenge due to its inherent resistance to hormonal and HER2-targeted therapies, resulting in a poor prognosis and limited treatment options beyond chemotherapy and immunotherapy. Consequently, the development of novel targeted therapies for this aggressive subtype is paramount, necessitating a deeper understanding of its underlying oncogenic mechanisms. We characterized the activities of regulatory elements such as promoters and enhancers, identifying a subset of enhancers that are specifically active in TNBC. Our follow-up studies found that distinct transcription factors (TFs) are differentially active in each tumor subtype, and that TFs such as FOXC1 activate TNBC-specific enhancers, leading to changes in the expression of genes involved in cancer progression. However, the precise mechanisms by which these subtype-specific TFs regulate target genes via enhancers remain poorly understood, particularly because enhancers can regulate distant genes and multiple target genes through three-dimensional chromatin looping. Moreover, it is unclear which proteins interact with FOXC1 specifically in TNBC. Elucidating the role of FOXC1 in oncogene regulation and targeting enhancer signaling pathways may provide new therapeutic strategies for reversing the aggressive phenotype of TNBC. Moreover, evaluating the relationship between FOXC1 dysregulation and clinical outcomes across different patient populations may help address cancer health disparities. Overall, this analysis will define the key role that FOXC1 plays in TNBC and provide valuable insights to guide the development of future targeted therapies. Chung Lee, Huan Cao, Vannah Algador, Suhn Rhie. Characterizing FOXC1 dysregulation in triple-negative breast cancer to advance precision therapies and reduce cancer health disparities [abstract]. In: Proceedings of the 19th AACR Conference on the Science of Cancer Health Disparities; 2026 Oct 18-21; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2026;35(10 Suppl):Abstract nr C119.