Loss of Hypermethylated in Cancer 1 (HIC1) in breast cancer cells contributes to stress-induced migration and invasion through β-2 adrenergic receptor (ADRB2) misregulation

J Biol Chem. 2012 Feb 17;287(8):5379-89. doi: 10.1074/jbc.M111.304287. Epub 2011 Dec 22.

Abstract

The transcriptional repressor HIC1 (Hypermethylated in Cancer 1) is a tumor suppressor gene inactivated in many human cancers including breast carcinomas. In this study, we show that HIC1 is a direct transcriptional repressor of β-2 adrenergic receptor (ADRB2). Through promoter luciferase activity, chromatin immunoprecipitation (ChIP) and sequential ChIP experiments, we demonstrate that ADRB2 is a direct target gene of HIC1, endogenously in WI-38 cells and following HIC1 re-expression in breast cancer cells. Agonist-mediated stimulation of ADRB2 increases the migration and invasion of highly malignant MDA-MB-231 breast cancer cells but these effects are abolished following HIC1 re-expression or specific down-regulation of ADRB2 by siRNA treatment. Our results suggest that early inactivation of HIC1 in breast carcinomas could predispose to stress-induced metastasis through up-regulation of the β-2 adrenergic receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Breast Neoplasms / physiopathology
  • Cell Adhesion / genetics
  • Cell Line, Tumor
  • Cell Movement* / genetics
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Humans
  • Kruppel-Like Transcription Factors / deficiency
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Receptors, Adrenergic, beta-2 / deficiency
  • Receptors, Adrenergic, beta-2 / genetics*
  • Stress, Physiological* / genetics

Substances

  • ADRB2 protein, human
  • HIC1 protein, human
  • Kruppel-Like Transcription Factors
  • RNA, Small Interfering
  • Receptors, Adrenergic, beta-2