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Cancer Res. 2018 Jan 15;78(2):422-435. doi: 10.1158/0008-5472.CAN-17-1533. Epub 2017 Nov 29.

HER2-Driven Breast Tumorigenesis Relies upon Interactions of the Estrogen Receptor with Coactivator MED1.

Author information

1
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
2
Graduate Program in Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
3
Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
4
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
5
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio. zhangxt@ucmail.uc.edu.

Abstract

Studies of the estrogen receptor (ER) coactivator protein Mediator subunit 1 (MED1) have revealed its specific roles in pubertal mammary gland development and potential contributions to breast tumorigenesis, based on coamplification of MED1 and HER2 in certain breast cancers. In this study, we generated a mouse model of mammary tumorigenesis harboring the MMTV-HER2 oncogene and mutation of MED1 to evaluate its role in HER2-driven tumorigenesis. MED1 mutation in its ER-interacting LxxLL motifs was sufficient to delay tumor onset and to impair tumor growth, metastasis, and cancer stem-like cell formation in this model. Mechanistic investigations revealed that MED1 acted directly to regulate ER signaling through the downstream IGF1 pathway but not the AREG pathway. Our findings show that MED1 is critical for HER2-driven breast tumorigenesis, suggesting its candidacy as a disease-selective therapeutic target.Significance: These findings identify an estrogen receptor-binding protein as a critical mediator of HER2-driven breast tumorigenesis, suggesting its candidacy as a disease-selective therapeutic target. Cancer Res; 78(2); 422-35. ©2017 AACR.

PMID:
29187405
PMCID:
PMC5771879
DOI:
10.1158/0008-5472.CAN-17-1533
[Indexed for MEDLINE]
Free PMC Article

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