title: Secreted factors derived from obese visceral adipose tissue regulate the expression of breast malignant transformation genes.
abstract: OBJECTIVE
  Obese adipose tissue, especially the visceral depot, exhibits altered production of several molecules that could have a role on the initiation/promotion of breast cancer development. The aim of this work was to evaluate the effect of excess adipose tissue and its secreted factors on the expression of genes involved in the early steps of tumor promotion on the mammary gland.
  
  
  METHODS
  Carcinogenesis-related gene expression was evaluated in mammary gland tissue from female diet-induced obese (DIO) Sprague-Dawley rats and circulating leukocytes isolated from a group of breast cancer diagnosed and non-diagnosed obese women and compared with their normal weight counterparts. In addition, the human non-tumoral mammary epithelial cell line MCF10A was treated in vitro with the visceral (retroperitoneal adipose tissue (RPAT)) or subcutaneous adipose tissue (SAT) secretome and with rising concentrations of the lipid peroxidation by-product 4-hydroxynonenal (4-HNE).
  
  
  RESULTS
  DIO rats were classified as susceptible to DIO (DIO-S) or partially resistant to DIO (DIO-R) according to the maximum fat mass gain of the lean group as a cut-off. As compared with lean and DIO-R, the DIO-S group showed a higher fat mass and lower lean mass. The anatomical characteristic of DIO-S was correlated with differential expression of cellular proliferation (ALDH3A1 and MYC) and antioxidant and DNA protection (GSTM2, SIRT1), and tumor suppression (TP53, PTEN, TGFB1) genes. Remarkably, this carcinogenesis-related gene expression pattern was reproduced in MCF10A treated with the RPAT secretome from DIO-S rats and with the lipid peroxidation by-product 4-HNE. Moreover, this pattern was also detected in leukocytes from obese women compared with normal weight women without evidence of breast cancer.
  
  
  CONCLUSIONS
  Lipid peroxides secreted by the obese visceral adipose tissue could be among the relevant factors that promote changes involved in the early steps of tumor development in mammary gland. These changes can be detected even before histological alterations and in circulating leukocytes.
authors.affiliation: Laboratory of Molecular and Cellular Endocrinology, Instituto de Investigación Sanitaria (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS) and Santiago de Compostela University (USC), Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Madrid, Spain.
authors.forename: A B
authors.initials: AB
authors.lastname: Crujeiras
authors.affiliation: Laboratory of Molecular and Cellular Endocrinology, Instituto de Investigación Sanitaria (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS) and Santiago de Compostela University (USC), Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Madrid, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Cabia
authors.affiliation: Laboratory of Molecular and Cellular Endocrinology, Instituto de Investigación Sanitaria (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS) and Santiago de Compostela University (USC), Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Madrid, Spain.
authors.forename: M C
authors.initials: MC
authors.lastname: Carreira
authors.affiliation: Laboratory of Molecular and Cellular Endocrinology, Instituto de Investigación Sanitaria (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS) and Santiago de Compostela University (USC), Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Amil
authors.affiliation: Division of Medical Oncology, Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Cueva
authors.affiliation: Laboratory of Molecular and Cellular Endocrinology, Instituto de Investigación Sanitaria (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS) and Santiago de Compostela University (USC), Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Madrid, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Andrade
authors.affiliation: Grupo Fisiopatologia Endocrina, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Madrid, Spain.
authors.forename: L M
authors.initials: LM
authors.lastname: Seoane
authors.affiliation: Grupo Obesidomica, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Madrid, Spain.
authors.forename: M
authors.identifier: http://orcid.org/0000-0002-9967-1650
authors.initials: M
authors.lastname: Pardo
authors.affiliation: Laboratory of Molecular and Cellular Endocrinology, Instituto de Investigación Sanitaria (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS) and Santiago de Compostela University (USC), Santiago de Compostela, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Sueiro
authors.affiliation: Division of General Surgery, Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Baltar
authors.affiliation: Clinical and Experimental Endocrinology, Department of Anatomy, Multidisciplinary Unit for Biomedical Research (UMIB), ICBAS, University of Porto, Porto, Portugal.
authors.forename: T
authors.initials: T
authors.lastname: Morais
authors.affiliation: Clinical and Experimental Endocrinology, Department of Anatomy, Multidisciplinary Unit for Biomedical Research (UMIB), ICBAS, University of Porto, Porto, Portugal.
authors.forename: M P
authors.initials: MP
authors.lastname: Monteiro
authors.affiliation: Division of Medical Oncology, Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Lopez-Lopez
authors.affiliation: Laboratory of Molecular and Cellular Endocrinology, Instituto de Investigación Sanitaria (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS) and Santiago de Compostela University (USC), Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Madrid, Spain.
authors.forename: F F
authors.initials: FF
authors.lastname: Casanueva
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D009363:Neoplasm Proteins / Q000378:metabolism*; D009765:Obesity / Q000473:pathology*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D050151:Subcutaneous Fat / Q000473:pathology*
chemical_list: D009363:Neoplasm Proteins