Interaction of developmental transcription factor HOXC11 with steroid receptor coactivator SRC-1 mediates resistance to endocrine therapy in breast cancer [corrected]

Cancer Res. 2010 Feb 15;70(4):1585-94. doi: 10.1158/0008-5472.CAN-09-3713. Epub 2010 Feb 9.

Abstract

Mechanisms of acquired resistance to endocrine therapy in breast cancer, a major clinical challenge, are poorly understood. We have used a mass spectrometry-based screen to identify proteins that are associated with the endocrine-resistant phenotype. In this study, we report the identification of a novel pathway of resistance to endocrine therapy involving interactions of the developmental transcription HOXC11 with the steroid receptor coactivator protein SRC-1, which is a strong predictor of reduced disease-free survival in breast cancer patients. HOXC11 and SRC-1 cooperate to regulate expression of the calcium-binding protein S100beta in resistant breast cancer cells. Nuclear HOXC11 and S100beta were found to strongly predict poor disease-free survival in breast cancer patients (n = 560; hazard ratios: 5.79 and 5.82, respectively; P < 0.0001). Elevated serum levels of S100beta detected in patients also predicted reduced disease-free survival (n = 80; hazard ratio: 5.3; P = 0.004). Our findings define a biomolecular interaction network that drives an adaptive response to endocrine therapy with negative consequences for survival in breast cancer.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Case-Control Studies
  • Disease-Free Survival
  • Drug Resistance, Neoplasm* / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks / physiology
  • Genes, Developmental / physiology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Nerve Growth Factors / blood
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism
  • Nuclear Receptor Coactivator 1 / genetics
  • Nuclear Receptor Coactivator 1 / metabolism*
  • Prognosis
  • Protein Binding / physiology
  • S100 Calcium Binding Protein beta Subunit
  • S100 Proteins / blood
  • S100 Proteins / genetics
  • S100 Proteins / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents, Hormonal
  • HOXC11 protein, human
  • Homeodomain Proteins
  • Nerve Growth Factors
  • S100 Calcium Binding Protein beta Subunit
  • S100 Proteins
  • Transcription Factors
  • NCOA1 protein, human
  • Nuclear Receptor Coactivator 1