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Cyclin D1 is necessary but not sufficient for anchorage-independent growth of rat mammary tumor cells and is associated with resistance of the Copenhagen rat to mammary carcinogenesis

Oncogene volume 22, pages 3452–3462 (2003)Cite this article

Abstract

To identify genes associated with the resistance of Copenhagen (Cop) rats to mammary carcinogenesis, we infused a retrovirus harboring v-Ha-ras directly into the main mammary ducts of resistant F1 rats from a cross between Cop and susceptible Wistar Furth (WF) rats. Adenocarcinomas formed in approximately 50% of infused glands. Cell lines derived from these tumors were clonal, but did not share a common viral integration site, suggesting that a high level of v-Ha-ras expression was able to overcome resistance in the F1 rats. Some of the cell lines were able to grow in soft agar, but a significant number did not display anchorage-independent growth. These growth characteristics were independent of v-Ha-ras expression levels. The ability to grow in soft agar was associated with the size of tumors induced by injecting the cells into nude mice, and showed a striking positive association with the expression of cyclin D1. Furthermore, while resistance to anchorage-independent growth was fully overcome by transfection of cyclin D1 in some clones, in the others the effect was partial. A similar pattern of cyclin D1 upregulation and growth in soft agar was also observed when the cells were transfected with an active form of β-catenin. Hybrid cells from the somatic fusion of an anchorage-dependent to an anchorage-independent clone did not grow in soft agar. These results suggest that while a high expression level of cyclin D1 is necessary for anchorage-independent growth in all clones, it is not sufficient for full growth capacity in soft agar, raising the possibility that the loss of a tumor suppressor gene in the cell lines is required to fully confer anchorage-independent growth. Our anchorage-dependent and -independent rat mammary tumor-derived cell lines may recapitulate the resistance and susceptibility of Cop and WF rats, respectively, to mammary carcinogenesis that could facilitate the identification of breast cancer susceptibility genes.

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Acknowledgements

We thank Dr B Vogelstein for the β-catenin plasmid and Dr IB Weinstein for the cyclin D1 plasmid. We also thank Drs J Filmus and Kirill Rosen for their constructive comments on the manuscript and Robin Duncan for help with the experiments with nude mice. This work was supported by a grant from the Canadian Breast Cancer Research Initiative.

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Author notes

  1. James E Korkola

    Present address: Cancer Center, University of California, San Francisco, CA, 94143- 0808, USA

Authors and Affiliations

  1. Molecular and Cell Biology Research, Sunnybrook and Women's College Health Sciences Centre, Toronto, ON, Canada

    You-Jun Li & Yaacov Ben-David

  2. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    You-Jun Li, James E Korkola, Michael C Archer & Yaacov Ben-David

  3. Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada

    Runlan Song & Michael C Archer

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  1. You-Jun Li
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Correspondence to Yaacov Ben-David.

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Li, YJ., Song, R., Korkola, J. et al. Cyclin D1 is necessary but not sufficient for anchorage-independent growth of rat mammary tumor cells and is associated with resistance of the Copenhagen rat to mammary carcinogenesis. Oncogene 22, 3452–3462 (2003). https://doi.org/10.1038/sj.onc.1206411

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