Androgen receptor-induced tumor suppressor, KLLN, inhibits breast cancer growth and transcriptionally activates p53/p73-mediated apoptosis in breast carcinomas

Hum Mol Genet. 2013 Jun 1;22(11):2263-72. doi: 10.1093/hmg/ddt077. Epub 2013 Feb 14.

Abstract

Androgen receptor (AR) expression by immunohistochemistry correlates with better prognosis and survival among breast cancer patients. We and others have shown that AR inhibits proliferation and induces apoptosis in breast cancer cells. However, the mechanism of AR's anti-tumor effect in breast cancer is still not fully understood. Our recent study indicates that AR upregulates expression of tumor suppressor gene PTEN by promoter activation in breast cancer. KLLN, encoding KLLN protein, is a newly identified gene, which shares a bidirectional promoter with PTEN and is transcribed in the opposite direction. So far, the function of KLLN has never been studied in tumorigenesis. Here, we define KLLN as a tumor suppressor in breast carcinomas, which inhibits tumor growth and invasiveness. After analyzing 188 normal breast and 1247 malignant breast cancer tissues, we observed the loss of KLLN in multiple breast cancer subtypes and this decreased KLLN expression associates with tumor progression and increasing histological grade in invasive carcinomas. We characterize KLLN, for the first time, as a transcription factor, directly promoting the expression of TP53 and TP73, with consequent elevated apoptosis and cell cycle arrest in breast cancer cells. We demonstrate, in vitro and in murine xenograph models, that both KLLN and PTEN are AR-target genes, mediating androgen-induced growth inhibition and apoptosis in breast cancer cells. Our observations suggest that KLLN might be used as a potential prognostic marker and novel therapy target for breast carcinomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Androgens / pharmacology
  • Animals
  • Apoptosis / genetics
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Carcinoma / genetics*
  • Carcinoma / metabolism*
  • Carcinoma / pathology
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mice
  • Middle Aged
  • Neoplasm Grading
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Receptors, Androgen / metabolism*
  • Transcriptional Activation
  • Tumor Protein p73
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Androgens
  • DNA-Binding Proteins
  • KLLN protein, human
  • Nuclear Proteins
  • Receptors, Androgen
  • TP73 protein, human
  • Trp73 protein, mouse
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins