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Cross-talk between HER2 and MED1 Regulates Tamoxifen Resistance of Human Breast Cancer Cells

Publication ,  Journal Article
Cui, J; Germer, K; Wu, T; Wang, J; Luo, J; Wang, S-C; Wang, Q; Zhang, X
Published in: Cancer Research
November 1, 2012

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. Cancer Res; 72(21); 5625–34. ©2012 AACR.

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Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

November 1, 2012

Volume

72

Issue

21

Start / End Page

5625 / 5634

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 1112 Oncology and Carcinogenesis
 

Citation

APA
Chicago
ICMJE
MLA
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Cui, J., Germer, K., Wu, T., Wang, J., Luo, J., Wang, S.-C., … Zhang, X. (2012). Cross-talk between HER2 and MED1 Regulates Tamoxifen Resistance of Human Breast Cancer Cells. Cancer Research, 72(21), 5625–5634. https://doi.org/10.1158/0008-5472.can-12-1305
Cui, Jiajun, Katherine Germer, Tianying Wu, Jiang Wang, Jia Luo, Shao-chun Wang, Qianben Wang, and Xiaoting Zhang. “Cross-talk between HER2 and MED1 Regulates Tamoxifen Resistance of Human Breast Cancer Cells.” Cancer Research 72, no. 21 (November 1, 2012): 5625–34. https://doi.org/10.1158/0008-5472.can-12-1305.
Cui J, Germer K, Wu T, Wang J, Luo J, Wang S-C, et al. Cross-talk between HER2 and MED1 Regulates Tamoxifen Resistance of Human Breast Cancer Cells. Cancer Research. 2012 Nov 1;72(21):5625–34.
Cui, Jiajun, et al. “Cross-talk between HER2 and MED1 Regulates Tamoxifen Resistance of Human Breast Cancer Cells.” Cancer Research, vol. 72, no. 21, American Association for Cancer Research (AACR), Nov. 2012, pp. 5625–34. Crossref, doi:10.1158/0008-5472.can-12-1305.
Cui J, Germer K, Wu T, Wang J, Luo J, Wang S-C, Wang Q, Zhang X. Cross-talk between HER2 and MED1 Regulates Tamoxifen Resistance of Human Breast Cancer Cells. Cancer Research. American Association for Cancer Research (AACR); 2012 Nov 1;72(21):5625–5634.

Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

November 1, 2012

Volume

72

Issue

21

Start / End Page

5625 / 5634

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 1112 Oncology and Carcinogenesis