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Loss of p21WAF1/CIP1 accelerates Ras oncogenesis in a transgenic/knockout mammary cancer model

Oncogene volume 19, pages 5338–5347 (2000)Cite this article

Abstract

Upregulation of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 and subsequent cell growth arrest or senescence is one mechanism by which normal cells are believed to respond to stress induced by the constitutively activated GTPase Ras. We hypothesize that in the absence of p21, the onset of Ras-dependent oncogenesis is accelerated. To test this hypothesis, we crossed MMTV/v-Ha-ras transgenic mice into a p21-deficient background. By 63 days of age, all 8 ras/p21−/− mice developed either malignant (mammary and/or salivary adenocarcinomas) or benign (Harderian hyperplasia) tumors. In contrast, by the same age, only one out of nine of the ras/p21+/+ mice developed a tumor. Furthermore, by 94 days of age, half of the ras/p21−/− mice, but none of the ras/p21+/+ mice, developed mammary tumors. p21-deficiency also accelerated the development of salivary (T50=66 days for ras/p21−/− vs T50=136 days for ras/p21+/+) and Harderian (T50=52 days for ras/p21−/− vs T50>221 days for ras/p21+/+) tumors. Furthermore, two out of the eight ras/p21−/− mice had metastatic lesions, one in its lungs, the other in its abdomen. None of the nine ras/p21+/+ mice had metastatic lesions. By 4 months of age, the mammary tumor multiplicity was 10-fold greater in ras/p21−/− (average 3.40 tumors/mouse) than in ras/p21+/+ (average 0.33 tumor/mouse) mice. However, once the tumors appeared, their growth rate, apoptosis level, and mitotic index were not affected by the loss of p21, suggesting that loss of p21 is critical in early but not late eventsof Ras oncogenesis. Altogether, the results show that tumor onset in MMTV/v-Ha-ras mice is p2l-dependent with loss of p2l associated with earlier tumor appearance and increased tumor multiplicity and aggressiveness.

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Acknowledgements

We thank Dr Tyler Jacks (Massachusetts Institute of Technology, Cambridge, Massachusetts, USA) for providing the p21 knockout mice, Sandy Livingston for excellent technical assistance with immunohistochemistry experiments, and Ed Haller for assistance with Ki-67 quantitation. We also thank the Pathology Core and the Molecular Imaging Core for technical assistance. This work was supported by NIH Grant CA67771 to SM Sebti, NIH Grant CA72694 to WJ Pledger and NIH Grant CA78038 to SM Sebti and WJ Pledger. RJ Jackson is supported by ACS Grant PF-99-320-01-CNE. WJ Pledger is supported by the Cortner-Couch Endowed Chair for Cancer Research.

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Author notes

  1. Jalila Adnane and Rosalind J Jackson: J Adnane and RJ Jackson contributed equally to this work.

Authors and Affiliations

  1. Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, College of Medicine, University of South Florida, 12902 Magnolia Drive, Tampa, 33612, Florida, FL, USA

    Jalila Adnane & Saïd M Sebti

  2. Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, College of Medicine, University of South Florida, 12902 Magnolia Drive, Tampa, 33612, Florida, FL, USA

    Rosalind J Jackson & W Jack Pledger

  3. Biostatics and Informatics Core, H. Lee Moffitt Cancer Center and Research Institute, College of Medicine, University of South Florida, 12902 Magnolia Drive, Tampa, 33612, Florida, FL, USA

    Alan B Cantor

  4. Department of Oncology, H. Lee Moffitt Cancer Center and Research Institute, College of Medicine, University of South Florida, 12902 Magnolia Drive, Tampa, 33612, Florida, FL, USA

    Rosalind J Jackson, W Jack Pledger & Saïd M Sebti

  5. Department of Biochemistry and Molecular Biology, H. Lee Moffitt Cancer Center and Research Institute, College of Medicine, University of South Florida, 12902 Magnolia Drive, Tampa, 33612, Florida, FL, USA

    Jalila Adnane, W Jack Pledger & Saïd M Sebti

  6. Department of Pathology and Laboratory Medicine, H. Lee Moffitt Cancer Center and Research Institute, College of Medicine, University of South Florida, 12902 Magnolia Drive, Tampa, 33612, Florida, FL, USA

    Santo V Nicosia

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Adnane, J., Jackson, R., Nicosia, S. et al. Loss of p21WAF1/CIP1 accelerates Ras oncogenesis in a transgenic/knockout mammary cancer model. Oncogene 19, 5338–5347 (2000). https://doi.org/10.1038/sj.onc.1203956

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