Abstract
Breast cancer is the most common malignancy among women. Most of these cancers overexpress cyclin D1, a component of the core cell-cycle machinery. We previously generated mice lacking cyclin D1 using gene targeting. Here we report that these cyclin D1-deficient mice are resistant to breast cancers induced by the neu and ras oncogenes. However, animals lacking cyclin D1 remain fully sensitive to other oncogenic pathways of the mammary epithelium, such as those driven by c-myc or Wnt-1. Our analyses revealed that, in mammary epithelial cells, the Neu–Ras pathway is connected to the cell-cycle machinery by cyclin D1, explaining the absolute dependency on cyclin D1 for malignant transformation in this tissue. Our results suggest that an anti-cyclin D1 therapy might be highly specific in treating human breast cancers with activated Neu–Ras pathways.
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Acknowledgements
We thank R. Bronson, M. Ciemerych, L. Le Cam, B. Elenbaas, A. Leder, S. Jean, M. Lee, M. Mann, T. Mäkelä, B. Rollins and R. A. Weinberg for help; P. Leder for SH1.1 and 13Ma1a cell lines; J. Direnzo and M. Brown for the HC11 cell line; and R. A. Weinberg for pBabe-puro-Ras-V12 and pSVNeuT plasmids. This work was supported by a grant from NIH and by the DOD Breast Cancer Idea Award to P.S. Y.G. is partly supported by the NCI SPORE in Breast Cancer at the DFCI/Harvard Medical School. P.S. is a Barr New Investigator.
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Yu, Q., Geng, Y. & Sicinski, P. Specific protection against breast cancers by cyclin D1 ablation. Nature 411, 1017–1021 (2001). https://doi.org/10.1038/35082500
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DOI: https://doi.org/10.1038/35082500
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