Dissecting the role of inherited non-coding variants in the enhancer architecture of breast cancer

The National Cancer Institute awarded Centro Comprensivo De Cancer De La Universidad De Puerto Rico $591,360 on August 27, 2026, under the Cancer Cause and Prevention Research program (CFDA 93.393, Assistance Type: Project Grant) to dissect the role of inherited non-coding variants in the enhancer architecture of breast cancer.

The research investigates how inherited genetic variation alters enhancer function and transcriptional regulation in breast cancer, with specific focus on FOXA1, a pioneer transcription factor essential for estrogen receptor activity and endocrine therapy response. The project examines ancestry-specific protective variants, including a 6Q25 variant present only in individuals with genetic similarity to indigenous American ancestry, and explores functional interactions between FOXA1 and the pro-inflammatory transcription factor NFKB in aggressive tumors. The overarching hypothesis posits that inherited genetic variation alters enhancer function leading to predictable transcriptional profiles that underlie individual- and population-specific breast cancer risk and outcome.

Place of performance is Puerto Rico. The period of performance runs from the award date through July 31, 2031. The obligation amount is $591,360.

Abstract

Breast cancer is the most frequently diagnosed cancer among women and a major contributor to global cancer mortality, with persistent disparities in incidence and outcomes across populations. Although social and environmental factors contribute to these inequities, inherited genetic variation also shapes individual and population-specific risk. Genome-wide association studies (GWAS) have identified hundreds of risk loci, more than 90% of which LIE in non-coding regions, underscoring a critical role for gene regulatory elements. Yet the molecular mechanisms by which non-coding variants influence transcriptional regulation, and how these effects differ across ancestries, remain largely unknown. This R01 application focuses on defining how inherited non-coding variants alter enhancer function in breast cancer through their impact on FOXA1, a pioneer transcription factor essential for estrogen receptor (ER) activity and a key determinant of endocrine therapy response. Preliminary data from our group show that FOXA1 binding is enriched at breast cancer GWAS loci, including the ancestry-specific protective variant at 6Q25 present only in individuals with genetic similarity to indigenous american ancestry. These findings suggest FOXA1 as a central mediator linking inherited variation to transcriptional dysregulation and population-specific cancer risk. Additional data implicate functional interactions between FOXA1 and the pro-inflammatory transcription factor nfκb, particularly in aggressive tumors, suggesting that inflammatory signaling further modulates enhancer architecture. Our overarching hypothesis is that inherited genetic variation alters enhancer function leading to predictable transcriptional profiles that underlie individual- and population-specific breast cancer risk and outcome. We will test this hypothesis through a rigorous, integrative approach that combines population genetics, multi-omic profiling, and functional genomics. Aim 1 will determine how inherited variants influence FOXA1 binding and enhancer activity across genetically diverse breast tumors. Aim 2 will define how nfκb signaling modulates FOXA1 function and contributes to inflammatory, aggressive phenotypes in an ancestry-specific manner. In aim 3 we will functionally characterize regulatory variants from GWAS loci using massively parallel reporter assays, crispqtl, and crispr perturbations, prioritizing variants that are private to or enriched in specific populations. This project is strengthened by the complementary expertise of the MPI team: DR. Hector franco brings expertise in single-cell genomics, transcriptional regulation, and bioinformatics, while DR. Julie dutil contributes deep expertise in genetic epidemiology, population genetics, and breast cancer disparities. Additional support from external collaborators, including DR. Hyejung won (UNC chapel hill) in massively parallel reporter assays, DR. Doug cress (MOFFITT) in molecular oncology, and DR. José oliveras (ponce health sciences university) in breast cancer clinical care, further enhances the project's rigor and translational relevance. Taken together, these studies will uncover the ancestry-specific regulatory logic of FOXA1, establish mechanisms linking genetic variation to enhancer activity, and define how inflammation exacerbates disparities in breast cancer. By integrating population genetics, functional genomics, and tumor biology, this project will reveal novel, actionable targets for precision prevention and therapy across diverse populations.