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Deletion of p53 in human mammary epithelial cells causes chromosomal instability and altered therapeutic response

Oncogene volume 29, pages 4715–4724 (2010)Cite this article

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Abstract

The TP53 tumor suppressor gene is the most commonly mutated gene in human cancers. To evaluate the biological and clinical relevance of p53 loss, human somatic cell gene targeting was used to delete the TP53 gene in the non-tumorigenic epithelial cell line, MCF-10A. In all four p53−/− clones generated, cells acquired the capability for epidermal growth factor-independent growth and were defective in appropriate downstream signaling and cell cycle checkpoints in response to DNA damage. Interestingly, p53 loss induced chromosomal instability leading to features of transformation and the selection of clones with varying phenotypes. For example, p53-deficient clones were heterogeneous in their capacity for anchorage-independent growth and invasion. In addition, and of clinical importance, the cohort of p53-null clones showed sensitivity to chemotherapeutic interventions that varied depending not only on the type of chemotherapeutic agent, but also on the treatment schedule. In conclusion, deletion of the TP53 gene from MCF-10A cells eliminated p53 functions, as well as produced p53−/− clones with varying phenotypes possibly stemming from the distinct chromosomal changes observed. Such a model system will be useful to further understand the cancer-specific phenotypic changes that accompany p53 loss, as well as help to provide future treatment strategies for human malignancies that harbor aberrant p53.

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Acknowledgements

We thank Dr Fred Bunz for providing TP53 knockout vectors and advice, and Joel Greschock for advice on copy number analysis. This work was supported by: NIH grant T32DK067872 (MBW), Susan G Komen Breast Cancer Foundation PDF104506 (MIV), DOD Breast Cancer Predoctoral Training Award BC083057 (MM), The Avon Foundation, R01CA109274, The Breast Cancer Research Foundation (BHP), R01CA107331 and R01GM58888 (DJW) and Maryland Cigarette Restitution Fund (KEB).

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Authors and Affiliations

  1. University of Maryland Greenebaum Cancer Center, Baltimore, MD, USA

    M B Weiss, M I Vitolo, D J Weber & K E Bachman

  2. University of Maryland Graduate Program in Molecular Medicine, Baltimore, MD, USA

    M B Weiss

  3. Department of Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    M Mohseni

  4. Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    D M Rosen, S R Denmeade & B H Park

  5. Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA

    D J Weber & K E Bachman

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  1. M B Weiss
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Correspondence to B H Park, D J Weber or K E Bachman.

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Competing interests

Work by Drs Park and Weber has been funded by the NIH. Dr Park is a consultant for GlaxoSmithKline and has received research funding from GlaxoSmithKline though none of the work presented in this paper was funded by those funds. Dr Park is on the Scientific Advisory Board of Horizon Discovery LTD, and receives payment for these services. This is managed as per the Johns Hopkins School of Medicine Conflict of Interest Policy. Dr Denmeade is a Consultant and receives equity from GenSpera and Protox Therapeutics. Dr Bachman is currently employed by GlaxoSmithKline though all data presented in this paper were generated when Dr Bachman was a faculty member of the University of Maryland Greenebaum Cancer Center.

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Weiss, M., Vitolo, M., Mohseni, M. et al. Deletion of p53 in human mammary epithelial cells causes chromosomal instability and altered therapeutic response. Oncogene 29, 4715–4724 (2010). https://doi.org/10.1038/onc.2010.220

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