Figure 1.

Mechanisms linking obesity with breast cancer development and intervention strategies to break Obesity-Breast Cancer Links. Increased energy intake and low physical activity results in obesity. Excess adiposity causes systemic changes, such as increased circulating levels of insulin/IGF-1, aromatase activity, estrogen production, and leptin:adiponectin ratio. Local changes due to the hyperplasia and hypertrophy of adipocytes, leads to a pro-inflammatory response promoting the secretion of cytokines and inflammatory molecules. These systemic and local changes activate key signaling pathways (PI3K/AKT/mTOR, RAS/RAF/MAPK, and JAK/STAT). The complex interplay among all of these alterations generates a microenvironment favorable for breast epithelial cell transformation and increase breast cancer risk and progression. Dysfunctional adipocytes, distant and present within the tumor microenvironment, produce high levels of leptin that contributes to chronic inflammation and BC progression. Obesity promotes cell proliferation, migration and invasion, epithelial-mesenchymal transition (EMT), angiogenesis and recruitment of immune cells. Obesity increases myofibroblast content, which stiffens the extracellular matrix (ECM) and enhances cancer cell growth. All these effects stimulate the entry of invasive cells into the circulation and the subsequent metastatic colonization of distant organs, such as bone, lung, liver and brain. Nutritional interventions, such as calorie restricted diets with balanced protein content and intermittent fasting can break the obesity-BC links, the benefits of the dietary interventions can be further improved by increasing daily physical activity.