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Adipocyte and Cell Biology

Secreted factors derived from obese visceral adipose tissue regulate the expression of breast malignant transformation genes

International Journal of Obesity volume 40, pages 514–523 (2016)Cite this article

Subjects

Abstract

Background/Objectives:

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.

Subjects and 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.

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Acknowledgements

This work was supported by grants from the Fondo de Investigacion Sanitaria, INTRASALUD programme (PI10/02464), PI14/01012 research projects, and CIBERobn (CB06/003), Instituto de Salud Carlos III (ISCIII)-Subdireccion General de Evaluacion y Fomento de la Investigacion; Fondo Europeo de Desarrollo Regional (FEDER), and the Health Department of the Government Xunta de Galicia (GRC2014/034), Spain as well as Fundacion Lilly and Fundacion Mapfre. B Cabia was funded by a Santiago de Compostela University (USC)-Campus Vida predoctoral contract (ref. 011–020). AB Crujeiras was funded by the ISCIII through a research contract ‘Sara Borrell’ (C09/00365). We thank Patricia Viaño for their excellent technical support in develop the hematoxylin and eosin staining and Dr Tomas García-Caballero for his advise and encouragement in this study, as well as the patients who voluntarily took part in this study.

Author information

Author notes

  1. A B Crujeiras and B Cabia: These authors contributed equally to this work.

Authors and Affiliations

  1. 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

    A B Crujeiras, B Cabia, M C Carreira, M Amil, S Andrade, A Sueiro & F F Casanueva

  2. CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Madrid, Spain

    A B Crujeiras, B Cabia, M C Carreira, M Amil, S Andrade, L M Seoane, M Pardo & F F Casanueva

  3. Division of Medical Oncology, Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain

    J Cueva & R Lopez-Lopez

  4. Grupo Fisiopatologia Endocrina, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain

    L M Seoane

  5. Grupo Obesidomica, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain

    M Pardo

  6. Division of General Surgery, Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain

    J Baltar

  7. Department of Anatomy, Clinical and Experimental Endocrinology, Multidisciplinary Unit for Biomedical Research (UMIB), ICBAS, University of Porto, Porto, Portugal

    T Morais & M P Monteiro

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  1. A B Crujeiras
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  2. B Cabia
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Correspondence to A B Crujeiras.

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Crujeiras, A., Cabia, B., Carreira, M. et al. Secreted factors derived from obese visceral adipose tissue regulate the expression of breast malignant transformation genes. Int J Obes 40, 514–523 (2016). https://doi.org/10.1038/ijo.2015.208

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