New FADS diet for endocrine resistant breast cancer

Of the >280,000 women diagnosed with breast cancer (BrCa) in 2024, the majority will have estrogen receptor (ER) positive disease and will be treated with endocrine therapies (ET) for up to 10 years. Unfortunately, endocrine therapy resistance (ETR) develops over time in up to 30% of these women which is incurable and eventually leads to mortality despite additional targeted drugs and chemotherapy. Thus, there is an unmet need to discover modifiable factors that both prevent the development of ETR and/or impede disease progression. Environmental factors play a significant role in the development and progression of ETR. Among these, dietary n-3 polyunsaturated fatty acids (PUFAs) have a long yet controversial history of impacting breast cancer etiology. In particular, there is some discrepancy about the putative effects of “plant-based” n-3 PUFAs (alpha linolenic acid, ALA) and “marine based” n-3 PUFAs (eicosapentanoic acid, EPA; and docosahexanoic, DHA). ALA is converted to EPA/DHA in cells through a series of elongation and desaturation events catalyzed by fatty acid desaturases (FADS). Overabundance of PUFAs leads to their oxidation in the cell membrane and is a precursor for cellular damage and cell death. While preclinical and clinical studies demonstrate both types of n-3 PUFAs are associated with improved BrCa outcomes, the evidence is stronger with the marine-based n-3 PUFAs. We have generated a series of breast cancer cell lines resistant to common forms of ET. Studies in these cells have revealed a persistent ETR metabolic phenotype that includes: 1)  expression of a FADS2 isoform with high enzymatic activity; 2)  intracellular n-3 polyunsaturated fatty acids; 3)  cytoplasmic neutral lipid droplets (LDs); and 4)  lipid peroxidation /  antioxidant capacity. Our working hypothesis is that ETR BrCa cells leverage endogenous FADS2-dependent conversion of ALA to EPA and DHA (endogenous production) to support the macromolecular and energetic needs of growth and progression, while protecting the cells against the anti-tumor effects of EPA and DHA via preferential sequestering into LDs. In contrast, exogenous EPA and DHA exposure has anti-tumor effects via suppression of extracellular growth factor receptors, the suppression of BrCa FADS2 expression, and increasing fatty acid oxidation, production of reactive oxygen species (ROS), and lipid peroxidation. This proposal merges expertise in diet and nutrition, breast cancer endocrine resistance, and medical oncology to: 1) assess the impact of ALA and EPA+DHA on the growth and progression of ETR BrCa cells and tumors; and 2) determine the role of FADS2 in both the development and maintenance of the ETR phenotype. These studies will advance our understanding of how dietary plant-based and marine-based PUFAs differentially affect the development and maintenance of ETR breast cancer. They have the potential to inform specific nutritional and pharmacological interventions for improving disease outcomes in the large population of women at risk for or living with ETR BrCa. Project Number: 1U01CA296659-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Paul Maclean (+2 co-PIs) | Institution: UNIVERSITY OF COLORADO DENVER, Aurora, CO | Award Amount: $625,470 | Activity Code: U01 | Study Section: Special Emphasis Panel[ZRG1 CDPT-F (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11284960