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Genetic alterations of the p14ARF -hdm2-p53 regulatory pathway in breast carcinoma

G H Ho1, J E Calvano, M Bisogna

  • 1Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

Breast Cancer Research and Treatment
|May 5, 2001
PubMed

Insights

TP53 mutations are common in breast cancer, but alterations in the p14ARF-hdm2-p53 pathway are infrequent. This suggests alternative mechanisms may drive breast carcinogenesis despite infrequent p14ARF mutations or HDM2 amplification.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • TP53 is a critical tumor suppressor gene frequently mutated in human cancers.
  • HDM2 amplification and overexpression can inactivate p53, promoting tumorigenesis.
  • p14ARF, a product of the INK4A locus, inhibits HDM2, thereby preserving p53 function.

Purpose of the Study:

  • To investigate the role of the p14ARF-hdm2-p53 regulatory pathway in breast carcinoma.
  • To determine if p14ARF mutations or HDM2 gene amplification are alternative mechanisms of p53 inactivation in breast cancer.

Main Methods:

  • Mutational analysis of TP53 (exons 5-9) and p14ARF exon 1beta using PCR-SSCP and sequencing.
  • Evaluation of p14ARF mRNA expression via RT-PCR.
  • Detection of HDM2 gene amplification using differential PCR.

Main Results:

  • TP53 mutations were found in 50% of cell lines and 19% of tumors.
  • p14ARF exon 1beta deletions with no detectable mRNA occurred in 14% of cell lines.
  • HDM2 gene amplification was not detected in cell lines but found in 7% of tumors.
  • All analyzed breast tumors had intact p14ARF exon 1beta and expressed the mRNA.
  • Aberrations in the p14ARF-hdm2-p53 pathway were identified in 64% of cell lines and 25% of tumors, with TP53 mutation being most common.

Conclusions:

  • TP53 mutations are the predominant aberration in the p14ARF-hdm2-p53 pathway in breast cancer.
  • p14ARF mutations and HDM2 gene amplification appear to be uncommon mechanisms for p53 inactivation in breast carcinoma.
  • Deregulation of the p14ARF-hdm2-p53 pathway may occur through alternative mechanisms in breast carcinogenesis.

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