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Alternative mammary oncogenic pathways are induced by D-type cyclins; MMTV-cyclin D3 transgenic mice develop squamous cell carcinoma

Oncogene volume 22, pages 4425–4433 (2003)Cite this article

Abstract

The three human D-type cyclins, cyclin D1, D2 and D3 share the ability to bind to and activate cdk4 and 6. MMTV-cyclin D1 transgenic mice develop mainly adenocarcinoma, while MMTV-cyclin D2 mice show a lack of alveologenesis during pregnancy and only develop carcinoma at low frequency. The effect of cyclin D3 overexpression in mammary glands remains hitherto unknown. We generated MMTV-cyclin D3 transgenic mice and report here that they develop exclusively squamous cell carcinoma. We show that although cyclin D3 transgene expression was detected early in puberty, postnatal development and mammary gland proliferation were normal in virgin animals. In contrast, multiparous mice develop multiple foci of abnormal growth that correspond to various stages of squamous metaplasia. Therefore, our results support a role for cyclin D3 in squamous differentiation. In addition, we found that p16 expression during involution is abolished, while p27 expression increased in MMTV-cyclin D3 mice, two modifications that have been reported in the other MMTV-D-type cyclin transgenic models. Our observations indicate that despite biochemical redundancy in vitro and in vivo, D-type cyclins promote distinct oncogenic pathways.

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Acknowledgements

We are grateful to Drs Matthew O'Connell, Liliana Ossowski, Rafael Mira-Y-Lopez, George Acs and Samuel Waxman for critical reading of this manuscript. This grant was supported by an NHMRC grant to DG and by the Samuel Waxman Foundation.

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Author notes

  1. Doris Germain

    Present address: Department of Medicine, Mount Sinai School of Medicine, Madison Avenue, New York, NY, 10029-6574, USA

  2. Andreja Pirkmaier, Renee Dow and Soula Ganiatsas: These authors contributed equally to this work

Authors and Affiliations

  1. Iot, 3002, Victoria, Australia

    Andreja Pirkmaier, Renee Dow, Soula Ganiatsas, Kerry Warren, Anne Thompson, Joy Hendley & Doris Germain

  2. Pathology Department, Peter MacCallum Cancer Institute, St Andrew's Place, East Melbourne, 3002, Victoria, Australia

    Paul Waring

  3. Department of Biochemistry and Molecular Biology, University of Melbourne, 3010, Victoria, Australia

    Doris Germain

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Correspondence to Doris Germain.

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Pirkmaier, A., Dow, R., Ganiatsas, S. et al. Alternative mammary oncogenic pathways are induced by D-type cyclins; MMTV-cyclin D3 transgenic mice develop squamous cell carcinoma. Oncogene 22, 4425–4433 (2003). https://doi.org/10.1038/sj.onc.1206488

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