Impact of Intermittent Fasting on Triple-Negative Breast Cancer in Obesity: Insights into Cellular Pathways and Immune Modulation


Obesity, characterized by excessive fat accumulation detrimental to health, is escalating as a global epidemic. The World Health Organization (WHO) projects that 1.12 billion adults will be affected by obesity by 2030. This condition is well-established as a risk factor for numerous diseases, including diabetes, cardiovascular diseases, and various forms of cancer. Notably, obesity is linked to cancers such as pancreatic, endometrial, esophageal, rectal, kidney, liver, colon, gallbladder, breast, thyroid, and ovarian cancers. One-fifth of cancer deaths are influenced by obesity, largely due to the chronic inflammation it induces.

Health Disparities and Breast Cancer

Obesity contributes significantly to health disparities among ethnicities, with African American (AA) women experiencing the highest rates of obesity compared to other ethnic groups. Breast cancer, the most common type of cancer and the second leading cause of cancer deaths among women, shows significant survival rate disparities. The five-year survival rate for localized breast cancer is 99%, dropping to 85.8% for regional stages and plummeting to 29% for distant stages.

Breast cancer subtypes are classified based on immunohistochemical features: estrogen receptor (ER) positive (+), progesterone receptor (PR)+, and human epidermal growth factor receptor 2 (HER2) negative (−) luminal A (LA); ER+, PR+, and HER2+ luminal B (LB); ER-, PR-, and HER2+ HER2-enriched (HER2); and ER-, PR-, and HER2- basal-like (BL) subtypes. Triple-negative breast cancer (TNBC), lacking ER, PR, and HER2 expressions, is notably aggressive with high mortality due to the lack of targeted therapies. TNBC incidence rates are higher in AA women, contributing to poorer survival rates in this demographic.

Obesity and Triple-Negative Breast Cancer (TNBC)

Obesity is a known risk factor for postmenopausal breast cancer, particularly increasing the risk of TNBC through central obesity or abdominal fat accumulation. However, the association between obesity and TNBC remains controversial. The withdrawal of obesity burdens may improve survival rates in patients with obesity-related cancers. Intermittent fasting (IF) has emerged as a potential strategy to reduce obesity and improve health outcomes.

Intermittent Fasting: Mechanisms and Benefits

Intermittent fasting involves cycles of fasting and eating, making it more manageable than traditional calorie restriction. IF offers various health benefits, including reduced obesity, improved immune function, enhanced insulin sensitivity, upregulated autophagy and mitophagy, decreased oxidative stress and inflammation, and increased longevity. In cancer contexts, IF has been suggested to have anti-cancer properties, improve chemotherapy efficacy, reduce cancer incidence, support prevention, and protect against chemotherapy toxicity. Studies have shown that IF can reduce obesity burden and mammary tumor formation in animal models, though results vary across different cancer types.

IF and TNBC: Research Findings

A significant study investigated whether obesity affects TNBC progression and whether IF targets obesity-related TNBC. The study utilized diet-induced obese and orthotopic mammary fat pad implantation models to establish that IF can potentially serve as a cost-effective adjuvant therapeutic strategy for TNBC.

The study’s findings indicated that IF attenuates obesity-induced TNBC progression through multiple pathways, including disrupted cell cycles, diminished epithelial-mesenchymal transition (EMT), systemic reduction in glucose and cholesterol levels, decreased macrophage (Mφ) infiltration into the tumor immune contexture, and downregulated inflammatory factors in the tumor microenvironment. These results align with previous studies suggesting that obesity leads to poorer overall survival (OS) in TNBC patients, particularly among AA women, who are more likely to be obese and diagnosed with TNBC.

Lifestyle Interventions and TNBC

Lifestyle interventions such as IF, dietary alterations, and physical activity appear promising in targeting the obesity-TNBC axis by reducing obesity burdens. A systematic review showed that physical activity was associated with reduced breast cancer deaths in ER-positive tumors but had no significant effects on ER-negative tumors, indicating limited benefits for TNBC mortality.

IF’s Impact on Obesity and TNBC

Research demonstrated that IF is more effective in obese conditions compared to normal conditions, significantly decreasing body weight and tumor volume/weight in diet-induced obese mice. These findings were consistent with studies on fasting-mimicking diets (FMD) that showed reduced body weight and tumor volume in breast cancer models.

Cellular Mechanisms of IF in TNBC

In vitro and in vivo studies showed that fasting conditions disrupt cell cycles and migration by affecting cell cycle- and EMT-related proteins, impacting cell viability. Identifying fasting-sensitive and resistant cancer cell types could optimize IF as an adjuvant cancer treatment. IF was shown to target EMT-related proteins such as vimentin and β-catenin in TNBC cells, reducing their expression and thus potentially limiting cancer cell migration and invasion.

Systemic Effects of IF on Metabolic Parameters

IF was found to reduce high-fat diet (HFD)-induced blood glucose and cholesterol levels, consistent with clinical trials demonstrating reduced blood glucose levels in breast cancer patients undergoing IF. The fasting condition’s ability to lower plasma glucose may critically affect cancer cell survival due to the Warburg effect, where cancer cells exhibit enhanced glucose uptake and conversion to lactic acid.

Immune Modulation by IF in TNBC

The study highlighted that IF reduces Mφ accumulation in the tumor microenvironment, potentially decreasing chronic inflammation and suppressing TNBC progression. IF also modulates other immune cells and inflammatory factors, indicating its potential to enhance anti-tumor immunity.

Conclusion and Future Perspectives

The research underscores the critical role of IF in targeting obesity-induced TNBC progression by modifying the tumor microenvironment and systemic metabolic parameters. While the study’s mouse models provide valuable insights, further clinical studies are necessary to fully understand and optimize IF’s therapeutic potential for cancer patients. IF emerges as a promising strategy to enhance cancer treatment efficacy, improve patient outcomes, and reduce the obesity burden in cancer progression.

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