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NIH grant 1R01CA316861-01: Dissecting the Role of Inherited Non-Coding Variants in the Enhancer Architecture of Breast Cancer
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Julie Dutil. Award: $591360.
Start: 2026-08-27T00:00:00.
Project Summary
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.document fetched 2026-09-06 02:47