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Impaired p53 function leads to centrosome amplification, acquired ERα phenotypic heterogeneity and distant metastases in breast cancer MCF-7 xenografts

Oncogene volume 27, pages 3901–3911 (2008)Cite this article

Abstract

In this study, we establish an MCF-7 xenograft model that mimics the progression of human breast carcinomas typified by loss of p53 integrity, development of centrosome amplification, acquired estrogen receptor (ERα) heterogeneity, overexpression of Mdm2 and metastatic spread from the primary tumor to distant organs. MCF-7 cells with abrogated p53 function (vMCF-7Dnp53) maintained nuclear ERα expression and normal centrosome characteristics in vitro. However, following mitogen stimulation, they developed centrosome amplification and a higher frequency of aberrant mitotic spindles. Centrosome amplification was dependent on cdk2/cyclin activity since treatment with the small molecule inhibitor SU9516 suppressed centriole reduplication. In contrast to the parental MCF-7 cells, when introduced into nude mice as xenografts, tumors derived from the vMCF-7DNp53 cell line developed a strikingly altered phenotype characterized by increased tumor growth, higher tumor histopathology grade, centrosome amplification, loss of nuclear ERα expression, increased expression of Mdm-2 oncoprotein and resistance to the antiestrogen tamoxifen. Importantly, while MCF-7 xenografts did not develop distant metastases, primary tumors derived from vMCF-7DNp53 cells gave rise to lung metastases. Taken together, these observations indicate that abrogation of p53 function and consequent deregulation of the G1/S cell cycle transition leads to centrosome amplification responsible for breast cancer progression.

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Abbreviations

1GX:

cultures reestablished from xenografts

ACI:

August/Copenhagen/Irish

EGF:

epidermal growth factor

ERα:

estrogen receptor α

IGF:

insulin-like growth factor

PVDF:

polyvinylidene difluoride

vMCF-7DNp53:

a variant cell line derived from MCF-7 that expresses a recombinant dominant negative p53 mutation (Val134)

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Acknowledgements

This work was supported by NCI CA72836 to JLS, USAMRMC BC022276 to ABD and the Mayo Clinic School of Medicine.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Tumor Biology Program, Mayo Clinic College of Medicine, Rochester, MN, USA

    A B D'Assoro, R Busby, I D Acu, C Quatraro, D J Farrugia & J L Salisbury

  2. Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA

    C Allen & E Galanis

  3. Department of Laboratory Medicine and Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA

    M M Reinholz

  4. Radiation Oncology Research, Mayo Clinic College of Medicine, Rochester, MN, USA

    M A Schroeder

  5. Department of Biomedical Sciences, University of Catania, Catania, Italy

    A B D'Assoro & F Stivala

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  1. A B D'Assoro
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Correspondence to J L Salisbury.

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D'Assoro, A., Busby, R., Acu, I. et al. Impaired p53 function leads to centrosome amplification, acquired ERα phenotypic heterogeneity and distant metastases in breast cancer MCF-7 xenografts. Oncogene 27, 3901–3911 (2008). https://doi.org/10.1038/onc.2008.18

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