Expressions of individual PHDs associate with good prognostic factors and increased proliferation in breast cancer patients

Breast Cancer Res Treat. 2012 May;133(1):179-88. doi: 10.1007/s10549-011-1750-5. Epub 2011 Aug 30.

Abstract

Tumor hypoxia-inducible transcription factor (HIF) overexpression often associates with a poor prognosis. Stability of the HIF-α subunits is regulated by HIF prolyl 4-hydroxylases, PHD1-3. We assessed here immunohistochemical expression of PHD1-3 and HIF-1α and 2α in patients with invasive ductal breast carcinoma (n = 102) and correlated their expression levels with main clinical prognostic factors and survival. PHD1 expression correlated with high proliferation, and these tumors were mainly estrogen receptor-negative. PHD3 expression declined in tumors of large size, poor differentiation, and high proliferation. There was a tendency for increased breast cancer-specific survival and longer disease-free survival among patients with high tumor PHD2 expression. Surprisingly, PHD1-3 expression did not correlate with HIF-1α or HIF-2α downregulation. However, HIF-2α expression correlated independently with low tumor stage and HIF-1α expression had a tendency for decreased breast cancer-specific survival. PHD1 and 3 appear to be HIF-independent factors in breast cancer. Not all PHD1 associated proliferation is estrogen-dependent and it is associated with a poor prognosis of cancer. PHD3 may be an important regulator of apoptosis and it is mainly found in tumors with good prognosis. PHD2 expression is likely to be involved in increased survival.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal, Breast / metabolism*
  • Carcinoma, Ductal, Breast / mortality
  • Carcinoma, Ductal, Breast / pathology
  • Cell Nucleus / metabolism
  • Cell Proliferation*
  • Cohort Studies
  • Dioxygenases / genetics
  • Dioxygenases / metabolism*
  • Disease-Free Survival
  • Female
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Kaplan-Meier Estimate
  • Middle Aged
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Procollagen-Proline Dioxygenase / genetics
  • Procollagen-Proline Dioxygenase / metabolism*
  • Prognosis
  • Proportional Hazards Models
  • Regression Analysis

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • endothelial PAS domain-containing protein 1
  • Dioxygenases
  • EGLN1 protein, human
  • Procollagen-Proline Dioxygenase
  • EGLN2 protein, human
  • EGLN3 protein, human
  • Hypoxia-Inducible Factor-Proline Dioxygenases