title: A nude mouse model of obesity to study the mechanisms of resistance to aromatase inhibitors.
abstract: Obesity is a risk factor for breast cancer progression. Breast cancer patients who are overweight or obese or have excess abdominal fat have an increased risk of local or distant recurrence and cancer-related death. Hormone depletion therapies can also cause weight gain, exacerbating the risk for these patients. To understand the effect of obesity on hormone-dependent human breast cancer tumors, we fed ovariectomized athymic nude mice a diet containing 45% kcal fat and 17% kcal sucrose (high fat sucrose diet (HFSD)), 10% kcal fat (low fat diet (LFD)), or a standard chow diet (chow). The mice fed the HFSD developed metabolic abnormalities consistent with the development of obesity such as weight gain, high fasting blood glucose, and impaired glucose tolerance. These mice also developed hyperinsulinemia and insulin resistance. The obese mice also had a higher tumor growth rate compared to the lean mice. Furthermore, the obese mice showed a significantly reduced responsiveness to letrozole. To understand the role of obesity in this reduced responsiveness, we examined the effect of insulin on the growth of MCF-7Ca cells in response to estrogen or letrozole. The presence of insulin rendered MCF-7Ca cells less responsive to estrogen and letrozole. Exogenous insulin treatment of MCF-7Ca cells also resulted in increased p-Akt as well as ligand-independent phosphorylation of ERα. These findings suggest that diet-induced obesity may result in reduced responsiveness of tumors to letrozole due to the development of hyperinsulinemia. We conclude that obesity influences the response and resistance of breast cancer tumors to aromatase inhibitor treatment.
authors.affiliation: Department of PharmacologyDivision of BiostatisticsUniversity of Maryland School of Medicine, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland, USADepartment of Medicine and PhysiologyUniversity of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Schech
authors.affiliation: Department of PharmacologyDivision of BiostatisticsUniversity of Maryland School of Medicine, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland, USADepartment of Medicine and PhysiologyUniversity of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of PharmacologyDivision of BiostatisticsUniversity of Maryland School of Medicine, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland, USADepartment of Medicine and PhysiologyUniversity of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Goloubeva
authors.affiliation: Department of PharmacologyDivision of BiostatisticsUniversity of Maryland School of Medicine, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland, USADepartment of Medicine and PhysiologyUniversity of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: John
authors.initials: J
authors.lastname: McLenithan
authors.affiliation: Department of PharmacologyDivision of BiostatisticsUniversity of Maryland School of Medicine, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland, USADepartment of Medicine and PhysiologyUniversity of Maryland School of Medicine, Baltimore, Maryland, USA gsabnis@som.umaryland.edu.
authors.forename: Gauri
authors.initials: G
authors.lastname: Sabnis
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics; D004032:Diet; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004967:Estrogens / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000097:blood; D000077289:Letrozole; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000627:therapeutic use*; D009765:Obesity / Q000097:blood / Q000378:metabolism*; D010052:Ovariectomy; D014230:Triazoles / Q000627:therapeutic use*; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D001786:Blood Glucose; D004967:Estrogens; D007328:Insulin; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole; D001141:Aromatase; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2
keywords: MCF-7Ca xenografts; aromatase inhibitors; breast cancer; diet-induced-obesity