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.
© 2010 Japanese Cancer Association.
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