Alex Nicole Staat

Background:  Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately affects obese individuals, in part due to hyperactivation of insulin signaling and promotion of epithelial-mesenchymal transition (EMT). Current therapeutic options fail to adequately address the metabolic and immune dysregulation seen in obesity-driven TNBC, highlighting a need for new strategies. Previous studies suggest that non-pharmacologic dietary interventions may alter pro-tumor pathways including insulin signaling and EMT. However, mechanistic understanding of these interventions remains limited, particularly regarding their effects on immune modulation and tumor progression.

Objective:  This literature review explores how dietary interventions—specifically intermittent fasting (IF), caloric restriction (CR), time-restricted feeding (TRF), and fasting-mimicking diets (FMD)—modulate insulin signaling and EMT to suppress tumor growth and metastasis in TNBC of obese individuals.

Search Methods:  PubMed was searched for studies published between 2018–2025 using keywords including “intermittent fasting,” “caloric restriction,” “triple-negative breast cancer,” “insulin signaling,” and “epithelial-mesenchymal transition.” Relevant in vitro, in vivo, and clinical studies were selected based on their investigation of dietary intervention effects on TNBC.

Results:  In vitro studies using TNBC cell lines (MDA-MB-231, 4T1) demonstrated that fasting-mimicking conditions reduced proliferation by inducing G2/M cell cycle arrest via downregulation of Cyclin B1 and CDK1 phosphorylation, while reducing EMT markers like vimentin and suppressing AKT/mTOR signaling pathways.¹ In vivo mouse models subjected to IF, TRF, and CR revealed that these interventions significantly reduced tumor volume and metastasis through multiple mechanisms. TRF normalized insulin levels by ~25%, suppressed AKT and mTOR activity, and decreased expression of EMT genes including N-cadherin and fibronectin.³ Markedly, pharmacologic suppression of insulin secretion replicated the effects of TRF, while artificial insulin elevation negated them, directly implicating hyperinsulinemia as a driver of tumor progression.³ CR also enhanced the immune microenvironment by reducing regulatory T cells (Tregs) by 43% and increasing CD8+ T cell infiltration following radiation therapy.⁴ In clinical settings, FMD administered during chemotherapy led to a 25% increase in pathological complete response and reduced treatment toxicity by 30%.⁵ These benefits correlated with improved insulin sensitivity, reduced glucose levels, and enhanced CD8+ T cell infiltration with decreased Tregs.⁵ Mediterranean CR also demonstrated epigenetic remodeling by reducing DNA hypermethylation in genes regulating EMT and inflammation.²

Conclusion:  Dietary interventions such as IF, CR, TRF, and FMD modulate critical tumorigenic pathways in obesity-driven TNBC, notably insulin signaling and EMT, while concurrently reprogramming the immune microenvironment. These strategies demonstrate therapeutic promise as adjuncts to conventional treatments. Future research should focus on multi-omics profiling to personalize dietary-pharmacologic interventions and optimize long-term outcomes in TNBC patients.

Works Cited:

1. Son D-S, Done KA, Son J, et al. Intermittent Fasting Attenuates Obesity-Induced Triple-Negative Breast Cancer Progression by Disrupting Cell Cycle, Epithelial–Mesenchymal Transition, Immune Contexture, and Proinflammatory Signature. Nutrients. 2024;16(13):2101.
2. Bowers LW, Doerstling SS, Shamsunder MG, et al. Reversing the Genomic, Epigenetic, and Triple-Negative Breast Cancer-Enhancing Effects of Obesity. Cancer Prev Res (Phila). 2022;15(9):581-594.
3. Kumar D, et al. Time-restricted feeding normalizes hyperinsulinemia to inhibit breast cancer in obese postmenopausal mouse models. Nat Commun. 2021;12:565.
4. Manukian G, Kivolowitz C, DeAngelis T, et al. Caloric Restriction Impairs Regulatory T cells Within the Tumor Microenvironment After Radiation and Primes Effector T cells. Int J Radiat Oncol Biol Phys. 2021;110(5):1341-1349.
5. Caffa I, Spagnolo V, Vernieri C, et al. Fasting-mimicking diet and hormone therapy induce breast cancer regression. Nature. 2020;583:620–624.