Journal
CANCER RESEARCH
Volume 78, Issue 2, Pages 422-435Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-1533
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Funding
- Ohio Cancer Research Seed Money
- Cincinnati Cancer Center
- University of Cincinnati Cancer Institute Pilot Grants
- Ride Cincinnati Award
- Komen for the Cure Foundation Career Catalyst Grant [KG110028]
- American Cancer Society Research Scholar Grant [RSG-12-268-01]
- National Institutes of Health Grant [R01CA197865]
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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 receptorbinding protein as a critical mediator of HER2-driven breast tumorigenesis, suggesting its candidacy as a disease-selective therapeutic target. (C) 2017 AACR.
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