Overexpression of the EVI1 oncogene is associated typically with aggressive myeloid leukemia, but is also detectable in breast carcinoma (BC) where its contributions are unexplored. Analyzing a tissue microarray of 608 BC patient specimens, we documented EVI1 overexpression in both estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) BC. Here we report prognostic relevance of EVI1 overexpression in triple-negative BC (TNBC) but not in the HER2-positive BC subset. In human breast cancer cells, EVI1 silencing reduced proliferation, apoptosis resistance and tumorigenicity, effects rescued by estrogen supplementation in ER+ BC cells. Estrogen addition restored ERK phosphorylation in EVI1-silenced cells, suggesting that EVI1 and estradiol signaling merge in MAPK activation. Conversely, EVI1 silencing had no effect on consitutive ERK activity in HER2+ BC cells. Microarray analyses revealed G-protein coupled receptor (GPR) signaling as a prominent EVI1 effector mechanism in BC. Among others, the GPR54-ligand KISS1 was identified as a direct transcriptional target of EVI1, which together with other EVI1-dependent cell motility factors such as RHOJ regulated BC cell migration. Overall, our results establish the oncogenic contributions of EVI1 in ER- and HER2-negative subsets of breast cancer.
- Received March 1, 2016.
- Revision received November 29, 2016.
- Accepted January 8, 2017.
- Copyright ©2017, American Association for Cancer Research.