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Rb inactivation accelerates neoplastic growth and substitutes for recurrent amplification of cIAP1, cIAP2 and Yap1 in sporadic mammary carcinoma associated with p53 deficiency

Oncogene volume 29, pages 5700–5711 (2010)Cite this article

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A Correction to this article was published on 28 January 2021

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Abstract

Genetically defined mouse models offer an important tool to identify critical secondary genetic alterations with relevance to human cancer pathogenesis. We used newly generated MMTV-Cre105Ayn mice to inactivate p53 and/or Rb strictly in the mammary epithelium, and to determine recurrent genomic changes associated with deficiencies of these genes. p53 inactivation led to formation of estrogen receptor-positive raloxifene-responsive mammary carcinomas with features of luminal subtype B. Rb deficiency was insufficient to initiate carcinogenesis but promoted genomic instability and growth rate of neoplasms associated with p53 inactivation. Genome-wide analysis of mammary carcinomas identified a recurrent amplification at chromosome band 9A1, a locus orthologous to human 11q22, which contains protooncogenes cIAP1 (Birc2), cIAP2 (Birc3) and Yap1. It is interesting that this amplicon was preferentially detected in carcinomas carrying wild-type Rb. However, all three genes were overexpressed in carcinomas with p53 and Rb inactivation, likely due to E2F-mediated transactivation, and cooperated in carcinogenesis according to gene knockdown experiments. These findings establish a model of luminal subtype B mammary carcinoma, identify critical role of cIAP1, cIAP2 and Yap1 co-expression in mammary carcinogenesis and provide an explanation for the lack of recurrent amplifications of cIAP1, cIAP2 and Yap1 in some tumors with frequent Rb deficiency, such as mammary carcinoma.

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Acknowledgements

We thank David C Corney for critical reading of this paper and Dr Anton Berns (Netherlands Cancer Institute, Amsterdam, The Netherlands) for the generous gift of the p53floxP/floxP and RbfloxP/floxP mice. This work was supported by grants R01 CA96823 (NIH/NCI) and C023050 (NYSTEM) to AYN.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA

    L Cheng, Z Zhou, A Flesken-Nikitin, I A Toshkov & A Y Nikitin

  2. Microarray Core Facility, Cornell University, Ithaca, NY, USA

    W Wang

  3. Genetics Branch, National Cancer Institute, NIH, Bethesda, MD, USA

    J Camps & T Ried

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  1. L Cheng
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Correspondence to A Y Nikitin.

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Cheng, L., Zhou, Z., Flesken-Nikitin, A. et al. Rb inactivation accelerates neoplastic growth and substitutes for recurrent amplification of cIAP1, cIAP2 and Yap1 in sporadic mammary carcinoma associated with p53 deficiency. Oncogene 29, 5700–5711 (2010). https://doi.org/10.1038/onc.2010.300

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