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Wwox inactivation enhances mammary tumorigenesis

Oncogene volume 30, pages 3900–3906 (2011)Cite this article

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Abstract

Breast cancer is the leading cause of cancer-related death in women worldwide. Expression of the WWOX tumor suppressor is absent or reduced in a large proportion of breast tumors suggesting that loss of WWOX may contribute to breast tumorigenesis. Wwox-deficient mice die by 3–4 weeks of age precluding adult tumor analysis. To evaluate the effect of WWOX-altered expression on mammary tumor formation, the Wwox-heterozygous allele was back crossed onto the C3H mammary tumor-susceptible genetic background (WwoxC3H+/−) and incidence of mammary tumor formation was evaluated. Although 50% of the female WwoxC3H+/− mice developed mammary carcinomas, only 7% of WwoxC3H+/+ mice did. Intriguingly, mammary tumors in WwoxC3H+/− mice frequently lost WWOX protein expression suggesting a genetic predisposition toward mammary tumorigenesis. Immunohistochemical staining of hormone receptors revealed loss of estrogen receptor-α (ER) and progesterone receptor in the majority of these tumors. In vitro, depletion of WWOX in MCF7 ER-positive cells led to reduced ER expression and reduced sensitivity to tamoxifen and estrogen treatment and was associated with enhanced survival and anchorage-independent growth. Finally, cDNA array analyses of murine normal mammary epithelial cells and mammary tumors identified 163 significantly downreguated and 129 upregulated genes in the tumors. The majority of differentially expressed genes were part of pathways involved in cellular movement, cell-to-cell signaling and interaction, cellular development, cellular growth and proliferation and cell death. These changes in gene expression of mouse mammary tumors in WwoxC3H+/− mice resemble, at least in part, human breast cancer development. Our findings demonstrate the critical role that the WWOX tumor suppressor gene has in preventing tumorigenesis in breast cancer.

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Acknowledgements

We are grateful to all the Aqeilan's lab members for helpful suggestions and technical assistance. This research was supported by grants from NIH (R01DK060907) to ZN and RIA, Israeli Science Foundation (#1331/08) to RIA and Israel Cancer Research Funds (ICRF) to ZS.

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Authors and Affiliations

  1. Department of Immunology and Cancer Research-IMRIC, The Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel

    S K Abdeen, Z Salah, M Abu-Odeh & R I Aqeilan

  2. Department of Experimental Pathology, Hebrew University-Hadassah Medical School, Jerusalem, Israel

    B Maly

  3. Genomic Data Analysis Unit, Hebrew University-Hadassah Medical School, Jerusalem, Israel

    Y Smith

  4. Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, Miami, FL, USA

    R Tufail & Z Nawaz

  5. Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA

    N Zanesi & C M Croce

Authors
  1. S K Abdeen
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  2. Z Salah
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  3. B Maly
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  4. Y Smith
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  5. R Tufail
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  6. M Abu-Odeh
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  7. N Zanesi
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  8. C M Croce
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  9. Z Nawaz
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  10. R I Aqeilan
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Correspondence to R I Aqeilan.

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Supplementary Information accompanies the paper on the Oncogene website

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Abdeen, S., Salah, Z., Maly, B. et al. Wwox inactivation enhances mammary tumorigenesis. Oncogene 30, 3900–3906 (2011). https://doi.org/10.1038/onc.2011.115

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