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

Studies of the estrogen receptor (ER) coactivator protein MED1 have revealed its specific roles in pubertal mammary gland development and potential contributions to breast tumorigenesis, based on co-amplification 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 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 IGF-1 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.

http://ift.tt/2AmXs9s