Cross-talk between HER2 and MED1 regulates tamoxifen resistance of human breast cancer cells.

Abstract

Despite the fact that most breast cancer patients have estrogen receptor (ER) α-positive tumors, up to 50% of the patients are or soon develop resistance to endocrine therapy. It is recognized that HER2 activation is one of the major mechanisms contributing to endocrine resistance. In this study, we report that the ER coactivator MED1 is a novel cross-talk point for the HER2 and ERα pathways. Tissue microarray analysis of human breast cancers revealed that MED1 expression positively correlates most strongly with HER2 status of the tumors. MED1 was highly phosphorylated, in a HER2-dependent manner, at the site known to be critical for its activation. Importantly, RNAi-mediated attenuation of MED1 sensitized HER2-overexpressing cells to tamoxifen treatment. MED1 and its phosphorylated form, but not the corepressors N-CoR and SMRT, were recruited to the ERα target gene promoter by tamoxifen in HER2-overexpressing cells. Significantly, MED1 attenuation or mutation of MED1 phosphorylation sites was sufficient to restore the promoter recruitment of N-CoR and SMRT. Notably, we found that MED1 is required for the expression of not only traditional E2-ERα target genes but also the newly described EGF-ERα target genes. Our results additionally indicated that MED1 is recruited to the HER2 gene and required for its expression. Taken together, these findings support a key role for MED1 in HER2-mediated tamoxifen resistance and suggest its potential usage as a therapeutic target to simultaneously block both ERα and HER2 pathways for the treatment of this type of endocrine resistant breast cancer.

• Authors: Jiajun Cui, Katherine Germer, Tianying Wu, Jiang Wang, Jia Luo, Shao-chun Wang, Qianben Wang, Xiaoting Zhang
• Journal: Cancer research (Cancer Res) Vol. 72 Issue 21 Pg. 5625-34 (Nov 01 2012) ISSN: 1538-7445 [Electronic] United States
• PMID: 22964581 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• Antineoplastic Agents
• MED1 protein, human
• Mediator Complex Subunit 1
• Tamoxifen
• Receptor, ErbB-2

Topics

• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (genetics, metabolism)
• Cell Line, Tumor
• Chromatin Immunoprecipitation
• Drug Resistance, Neoplasm (physiology)
• Female
• Gene Expression Regulation, Neoplastic (genetics)
• Humans
• Immunohistochemistry
• MCF-7 Cells
• Mediator Complex Subunit 1 (genetics, metabolism)
• Real-Time Polymerase Chain Reaction
• Receptor Cross-Talk (physiology)
• Receptor, ErbB-2 (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Tamoxifen (pharmacology)
• Tissue Array Analysis
• Transfection