Combined fat and sugar intake reshapes the tumor microenvironment through hypoxia and lipogenic pathways in breast cancer.

PURPOSE: Breast cancer is the most prevalent malignancy worldwide. Beyond genetic factors, dietary components like palmitic acid (PA) and sucrose modulate tumor progression and microenvironment dynamics. However, their combined mechanistic impacts on tumor-stroma crosstalk remain undefined. We investigated how dietary PA and sucrose affect breast cancer growth and the tumor microenvironment using a murine model.

METHODS

Mice received Control, high-PA (HPOD), high-sucrose (HCD), or combined (HPCD) diets. We assessed tumor growth, metabolic parameters, membrane fatty acids, histopathology, proliferative indices, and microenvironment markers (CD8, F4/80, α-SMA, HIF-1α, FASN). In vitro assays evaluated PA and fructose effects on LM3 cells and fibroblasts.

RESULTS

HCD and HPCD markedly promoted tumor growth versus Control and HPOD. HPOD increased membrane saturated fatty acids, whereas HCD elevated ω-6 PUFAs. Both HCD and HPCD increased macrophage infiltration (F4/80 +), while HPCD specifically activated cancer-associated fibroblasts (α-SMA). HIF-1α protein increased across all experimental diets without mRNA alterations, suggesting post-transcriptional stabilization. FASN protein upregulation occurred in HCD and HPCD, while Fasn mRNA increased specifically in HCD. In vitro, combining PA and fructose enhanced LM3 cell proliferation and viability while reducing apoptosis. Additionally, this co-treatment specifically increased fibroblast viability.

CONCLUSIONS

Diets rich in PA and sucrose drive breast cancer progression through distinct mechanisms. Carbohydrates transcriptionally activate FASN-mediated lipogenesis, whereas their combination with PA remodels the tumor microenvironment via CAF activation and HIF-1α post-transcriptional stabilization. These findings highlight specific dietary components as critical variables in cancer progression, offering potential implications for nutritional interventions and targeted therapies.