title: 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-α, interleukin-6, and prostaglandin E2, 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro," Bari, Italy valeriasimo@gmail.com.
authors: Valeria
authors: V
authors: Simone
authors: Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro," Bari, Italy.
authors: Morena
authors: M
authors: D'Avenia
authors: Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro," Bari, Italy.
authors: Antonella
authors: A
authors: Argentiero
authors: Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro," Bari, Italy.
authors: Claudia
authors: C
authors: Felici
authors: Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro," Bari, Italy.
authors: Francesca Maria
authors: FM
authors: Rizzo
authors: Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro," Bari, Italy.
authors: Giovanni
authors: G
authors: De Pergola
authors: Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro," Bari, Italy.
authors: Franco
authors: F
authors: Silvestris
mesh_terms: D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D004967:Estrogens / Q000235:genetics; D005260:Female; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000235:genetics* / Q000473:pathology; D007333:Insulin Resistance / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000473:pathology; D017698:Postmenopause / Q000235:genetics; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D004967:Estrogens; C508600:IL6 protein, human; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Adipokines; Breast cancer; Insulin resistance; Obesity; Polymorphisms; Risk factors