Hakai acts as a coregulator of estrogen receptor alpha in breast cancer cells

Cancer Sci. 2010 Sep;101(9):2019-25. doi: 10.1111/j.1349-7006.2010.01636.x.

Abstract

Estrogen receptors play a key role in breast cancer development. One of the current therapeutic strategies for the treatment of estrogen receptor (ER)-α-positive breast cancers relies on the blockade of ERα transcriptional activity. In the present study, we characterized Hakai, originally characterized as an E-cadherin binding protein, as a strong blockade of ERα in breast cancer cells. We showed that Hakai inhibited the transcriptional activity of ERα by binding directly to ERα. The DNA-binding domain of ERα was found to be responsible for its interaction with Hakai. Hakai competed with ERα coactivators, such as steroid receptor coactivator-1 (SRC-1) and glucocoriticord receptor interacting protein-1 (GRIP-1), for the modulation of ERα transactivation, while its ubiquitin-ligase activity was not required. Further, overexpression of Hakai inhibited the proliferation and migration of breast cancer cells. Taken together, these results suggest that Hakai is a novel corepressor of ERα and may play a negative role in the development and progression of breast cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive / drug effects
  • Blotting, Western
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • COS Cells
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Chlorocebus aethiops
  • Estradiol / pharmacology
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Humans
  • Immunoprecipitation
  • Nuclear Receptor Coactivator 2 / genetics
  • Nuclear Receptor Coactivator 2 / metabolism
  • Nuclear Receptor Coactivator 3 / genetics
  • Nuclear Receptor Coactivator 3 / metabolism
  • Nuclear Receptor Coactivators / genetics
  • Nuclear Receptor Coactivators / metabolism*
  • Protein Binding / drug effects
  • Testosterone / pharmacology
  • Transcriptional Activation / drug effects
  • Transfection
  • Two-Hybrid System Techniques
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Estrogen Receptor alpha
  • Nuclear Receptor Coactivator 2
  • Nuclear Receptor Coactivators
  • Testosterone
  • Estradiol
  • NCOA3 protein, human
  • Nuclear Receptor Coactivator 3
  • CBLL1 protein, human
  • Ubiquitin-Protein Ligases