Obesity and Breast Cancer: Molecular Interconnections and Potential Clinical Applications

Abstract

Obesity is an important risk factor for breast cancer (BC) in postmenopausal women; interlinked molecular mechanisms might be involved in the pathogenesis. Increased levels of estrogens due to aromatization of the adipose tissue, inflammatory cytokines such as tumor necrosis factor-a, interleukin-6, and prostaglandin E 2 , insulin resistance and hyperactivation of insulin-like growth factors pathways, adipokines, and oxidative stress are all abnormally regulated in obese women and contribute to cancerogenesis. These molecular factors interfere with intracellular signaling in the mitogen-activated protein kinase and phosphatydilinositol-3-phosphate/mammalian target of rapamycin (mTOR) pathways, which regulate the progression of the cell cycle, apoptosis, and protein synthesis. In this context, structural defects of typical genes related to both BC and obesity, such as leptin, leptin receptor, serum paraoxonase/arylesterase 1, the fat mass and obesity-associated gene and melanocortin receptor 4, have been associated with a high or low risk of BC development.The early detection of these gene alterations might be useful as risk predictors in obese women, and targeting these pathways involved in the BC pathogenesis in obese women is a potential therapeutic tool. In particular, mTOR pathway deregulation concurs in both obesity and BC, and inhibition of this might disrupt the molecular interlinks in a similar manner to that of metformin, which exerts definite anticancer activity and is currently used as an antidiabetic drug with a weight-reducing property. The identification of both genetic and pharmacological implications on the prevention and management of BC is the ultimate aim of these studies. The Oncologist 2016;21:404-417 Implications for Practice: Obese women are at risk of breast cancer, but clinicians lack concrete tools for the prevention or early diagnosis of this risk.The present study, starting from the biology and the molecular defects characterizing both obesity and breast cancer, analyzed the potential molecules and genetic defects whose early identification could delineate a risk profile. Three steps are proposed that are potentially achievable in the clinical assessment of obese women, namely the evaluation of altered levels of serum molecules, the identification of genetic polymorphisms, and the study of the transcriptomic profile of premalignant lesions. Finally, the therapeutic implications of this molecular assessment were evaluated.

Distinct Effects of Body Mass Index and Waist/Hip Ratio on Risk of Breast Cancer by Joint Estrogen and Progestogen Receptor Status: Results from a Case-Control Study in Northern and Eastern China and Implications for Chemoprevention

“…Further studies are needed to reveal the potential mechanisms responsible for the effects of general and central obesity on breast cancer risk. These mechanisms are currently unclear, and interlinked molecular mechanisms have been supposed to be involved in the pathogenesis . Increased levels of free estrogens due to aromatization of adipose tissue, inflammatory cytokines such as tumor necrosis factor‐α, interleukin‐6, and prostaglandin E2, insulin resistance and hyperactivation of insulin‐like growth factors pathways, and adipokines such as adiponectin have all been reported to contribute to carcinogenesis.…”

Combined Effects of Eicosapentaenoic Acid and Adipocyte Renin–Angiotensin System Inhibition on Breast Cancer Cell Inflammation and Migration

“…Obesity is one of the major modifiable risk factors for BC, especially in postmenopausal women, and is associated with poor cancer outcomes and survival in patients with BC [2,3]. Moreover, as inflammation is an important underlying basis for both diseases, it is critical to understand its involvement in mechanism(s) of obesity-related BC [4]. In obesity, adipose tissue expands and becomes hypertrophic and hypoxic, with invasion of proinflammatory M1-type macrophages and exaggerated secretion of protumor adipocytokines [5].…”

Activator Protein-2β Promotes Tumor Growth and Predicts Poor Prognosis in Breast Cancer

“…As the most commonly diagnosed cancer type among women, breast cancer forms a major threat to women's health globally [1][2][3][4]. It is mainly divided into the following four molecular subtypes, luminal A, luminal B, basal-like/triple negative, and HER2 [5].…”