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Prognostic value of the hDMP1-ARF-Hdm2-p53 pathway in breast cancer

Oncogene volume 32, pages 4120–4129 (2013)Cite this article

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Abstract

Our recent study showed critical roles of Dmp1 as a sensor of oncogenic Ras, HER2/neu signaling and activation of the Arf-p53 pathway. To elucidate the role of human DMP1 (hDMP1) in breast cancer, one hundred and ten pairs of human breast cancer specimen were studied for the alterations of the hDMP1-ARF-Hdm2-p53 pathway with follow up of clinical outcomes. Loss of heterozygosity (LOH) of the hDMP1 locus was found in 42% of human breast carcinomas, while that of INK4a/ARF and p53 were found in 20 and 34%, respectively. Hdm2 amplification was found in 13% of the same sample, which was found independently of LOH for hDMP1. Conversely, LOH for hDMP1 was found in mutually exclusive fashion with that of INK4a/ARF and p53, and was associated with low Ki67 index and diploid karyotype. Consistently, LOH for hDMP1 was associated with luminal A category and longer relapse-free survival, while that of p53 was associated with non-luminal A and shorter survival. Thus, loss of hDMP1 could define a new disease category associated with prognosis of breast cancer patients. Human breast epithelial cells/cancer cells with wild-type p53 were sensitive to growth inhibition by activated Dmp1:ER while those that delete p14ARF or p53, and/or Hdm2 amplification showed partial or nearly complete resistance, indicating that p53 is a critical target for hDMP1 to exhibit its biological activity.

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Acknowledgements

We are grateful to R Weinberg for HMEC cells; C Sherr, and M Roussel for plasmid DNAs. We thank G Hawkins and Abdoulaye Diallo for LOH analyses of breast cancer samples. We also thank G Kucera for providing information on human breast cancer patients’ samples, Guangchao Sui, Tim Kute for helpful discussions, Guorui Deng, and Jordan Chapman for technical assistance. K Inoue is supported by ACS RSG-07-207-01-MGO, NIH/NCI 5R01CA106314, and by Director’s Challenge Award #20595 from WFUHS. P Taneja was supported by the Susan G Komen Foundation postdoctoral fellowship KG080179. D Maglic has been supported by DOD pre-doctoral fellowship BC100907.

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Author notes

  1. D Maglic, S Zhu, E A Fry and P Taneja: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, USA

    D Maglic, S Zhu, E A Fry, P Taneja, F Kai, R D Kendig, T Sugiyama, M C Willingham & K Inoue

  2. Department of Cancer Biology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, USA

    D Maglic, E A Fry, P Taneja, F Kai, R D Kendig, T Sugiyama, L D Miller & K Inoue

  3. Department of Graduate Program in Molecular Medicine, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, USA

    D Maglic, S Zhu & K Inoue

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  1. D Maglic
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Correspondence to K Inoue.

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Maglic, D., Zhu, S., Fry, E. et al. Prognostic value of the hDMP1-ARF-Hdm2-p53 pathway in breast cancer. Oncogene 32, 4120–4129 (2013). https://doi.org/10.1038/onc.2012.423

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