Journal article
Cross-talk between HER2 and MED1 regulates tamoxifen resistance of human breast cancer cells
Cancer research (Chicago, Ill.), Vol.72(21), pp.5625-5634
11/01/2012
DOI: 10.1158/0008-5472.CAN-12-1305
PMCID: PMC4141533
PMID: 22964581
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.
Details
- Title: Subtitle
- Cross-talk between HER2 and MED1 regulates tamoxifen resistance of human breast cancer cells
- Creators
- Jiajun Cui - University of CincinnatiKatherine Germer - University of CincinnatiTianying Wu - University of CincinnatiJiang Wang - University of CincinnatiJia Luo - University of KentuckyShao-chun Wang - University of CincinnatiQianben Wang - Ohio State UniversityXiaoting Zhang - University of Cincinnati
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.72(21), pp.5625-5634
- DOI
- 10.1158/0008-5472.CAN-12-1305
- PMID
- 22964581
- PMCID
- PMC4141533
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Grant note
- DK P30 DK078392 / NIDDK NIH HHS R00 CA126160 / NCI NIH HHS K07 CA138714 / NCI NIH HHS P30 DK078392 / NIDDK NIH HHS R01 CA151979 / NCI NIH HHS UL1RR026314 / NCRR NIH HHS R01 AA017226 / NIAAA NIH HHS UL1 RR026314 / NCRR NIH HHS R01 CA090385 / NCI NIH HHS
- Language
- English
- Date published
- 11/01/2012
- Academic Unit
- Pathology
- Record Identifier
- 9984201116002771
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