BACKGROUND: Breast cancer (BC) patients exhibit increased cardiovascular disease (CVD) risk independent of treatment, implicating BC tumor-related factors in CV pathology. Obesity exacerbates CVD risk with BC, and BC patients tend to be obese at diagnosis. Large artery (e.g., aorta) stiffening and associated pathological wall remodeling are established CVD risk factors, yet no therapeutic interventions exist to mitigate BC-mediated aortic stiffening and pathological remodeling. Intermittent fasting (IMF) – scheduled times of caloric restriction – has shown select benefits for promoting CV health with obesity, but its influence on BC-related aortic stiffening and pathological wall remodeling in the setting of obesity have yet to be determined. HYPOTHESIS: We hypothesized that BC, in the setting of obesity, would induce stiffening and pathological remodeling of the aorta, characterized by alterations in extracellular matrix (ECM)-specific and non-specific protein expression consistent with pathological wall remodeling, and that IMF would mitigate these adverse BC-driven phenotypes. METHODS: 5-week-old female Rag1-null mice were fed a high-fat diet ad libitum (lib) for 12 weeks. Mice were then ovariectomized, provided estrogen-supplemented water (0.75 µM), and implanted in the 4th mammary gland with patient derived human UCD12 ER+ BC cells, with or without human tumor-associated mammary fibroblasts, to establish ER+ BC tumor growth. BC tumor–bearing and non–tumor–bearing mice were randomized to one of two diet groups for 7 weeks — ad lib standard chow or IMF with standard chow (80% caloric restriction for 4 days followed by 30% for 3 days) — yielding four experimental groups: (1) Sham + ad lib (Control); (2) Sham + IMF; (3) BC + ad lib; and (4) BC + IMF. Aortic stiffness was measured ex vivo by elastic modulus. Aortic wall thickness, diameter, and elastin fragmentation was quantified using fluorescence microscopy. Proteomics was performed on aortic tissue using liquid chromatography and mass spectrometry. ECM proteins were analyzed directly, and non-matrisome proteins were evaluated using unbiased KEGG pathway enrichment and TRRUST transcription factor analysis. RESULTS: Elastic modulus was higher in BC + ad lib vs. Control (12828 ± 6349 vs. 6688 ± 1106 kPa; P = 0.003), which was mitigated with IMF (8530 ± 1919 kPa vs. Control, P = 0.65). Aorta diameter was unchanged but wall thickness was lower in BC + ad lib vs. Control (0.039 ± 0.004 vs. 0.051 ± 0.005 µm; P = 0.003), which was mitigated with IMF (0.045 ± 0.005 µm vs. Control; P = 0.42). Identified elastin fragmentation was higher in BC + ad lib vs. Control (7 ± 1.8 vs. 5 ± 0.9 total #; P = 0.04), which was mitigated with IMF (5 ± 1.4 total # vs. Controls; P = 0.98). ECM-targeted proteomics showed that BC + ad lib mice exhibited broad alterations in ECM glycoproteins, proteoglycans, and matrix regulators, including increased Nid1, Fgl2, and Plod1, and reduced Itih1, Col6a2, and Fgf2. KEGG and TRRUST analyses indicated that BC + ad lib shifted aortic tissue toward increased fatty acid biosynthesis and activated transcriptional programs associated with metabolic stress and adverse remodeling (e.g., Srebf1, Nr1h3, Pparg). These BC-induced proteomic changes were largely attenuated by IMF. CONCLUSION: BC in the setting of obesity induced large artery stiffening and altered aortic morphology associated with alterations in ECM protein composition and metabolic pathways consistent with pathological aortic remodeling. IMF mitigated these structural and proteomic changes, suggesting IMF may help prevent BC-driven deterioration of aortic function and structure. FUNDING: T32AG000279, R01CA258766, P30CA046934 & R00HL159241. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Nguyen et al. (Fri,) studied this question.