Original Article | Published:

Selective roles of E2Fs for ErbB2- and Myc-mediated mammary tumorigenesis

Oncogene volume 34, pages 119128 (02 January 2015) | Download Citation

Abstract

Previous studies have demonstrated that cyclin D1, an upstream regulator of the Rb/E2F pathway, is an essential component of the ErbB2/Ras (but not the Wnt/Myc) oncogenic pathway in the mammary epithelium. However, the role of specific E2fs for ErbB2/Ras-mediated mammary tumorigenesis remains unknown. Here, we show that in the majority of mouse and human primary mammary carcinomas with ErbB2/HER2 overexpression, E2f3a is up-regulated, raising the possibility that E2F3a is a critical effector of the ErbB2 oncogenic signaling pathway in the mammary gland. We examined the consequence of ablating individual E2fs in mice on ErbB2-triggered mammary tumorigenesis in comparison to a comparable Myc-driven mammary tumor model. We found that loss of E2f1 or E2f3 led to a significant delay in tumor onset in both oncogenic models, whereas loss of E2f2 accelerated mammary tumorigenesis driven by Myc-overexpression. Furthermore, southern blot analysis of final tumors derived from conditionally deleted E2f3−/loxP mammary glands revealed that there is a selection against E2f3−/− cells from developing mammary carcinomas, and that such selection pressure is higher in the presence of ErbB2 activation than in the presence of Myc activation. Taken together, our data suggest oncogenic activities of E2F1 and E2F3 in ErbB2- or Myc-triggered mammary tumorigenesis, and a tumor suppressor role of E2F2 in Myc-mediated mammary tumorigenesis.

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Acknowledgements

We thank L Rawahneh, J Moffitt and N Lovett for technical assistance with histology. We also thank OSUCCC Shared Resources for microarray and nucleic acid. This work was funded by NIH grants to GL (R01CA85619, R01CA82259, R01HD047470, R01 CA121275; P01CA097189). GL is a Pew Charitable Trust Scholar and a Leukemia and Lymphoma Society Scholar.

Author information

Author notes

    • L Wu

    Current address: Department of Microbiology and Molecular Genetics and Cancer Center, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.

    • A de Bruin

    Current address: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands.

    • L Wu
    •  & A de Bruin

    These authors contributed equally to this work.

Affiliations

  1. Department of Molecular Genetics, College of Biological Sciences, Ohio State University, Columbus, OH, USA

    • L Wu
    • , A de Bruin
    • , H Wang
    • , T Simmons
    • , W Cleghorn
    • , L E Goldenberg
    • , E Sites
    • , A Sandy
    • , A Trimboli
    •  & G Leone
  2. Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA

    • L Wu
    • , A de Bruin
    • , H Wang
    • , T Simmons
    • , W Cleghorn
    • , L E Goldenberg
    • , E Sites
    • , A Sandy
    • , A Trimboli
    •  & G Leone
  3. Department of Molecular Virology Immunology and Medical Genetics, College of Medicine, Ohio State University, Columbus, OH, USA

    • L Wu
    • , A de Bruin
    • , H Wang
    • , T Simmons
    • , W Cleghorn
    • , L E Goldenberg
    • , E Sites
    • , A Sandy
    • , A Trimboli
    •  & G Leone
  4. Center for Biostatistics, Ohio State University, Columbus, OH, USA

    • S A Fernandez
  5. Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA

    • C Eng
  6. Division of Hematology & Oncology, College of Medicine, Ohio State University, Columbus, OH, USA

    • C Shapiro

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to L Wu.

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DOI

https://doi.org/10.1038/onc.2013.511

Supplementary Information accompanies this paper on the Oncogene website (http://www.nature.com/onc)

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