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Prominent oncogenic roles of EVI1 in breast carcinoma


Abstract

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.

Abstract

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:16 February 2017
Deposited On:27 Feb 2017 10:29
Last Modified:23 Nov 2017 16:21
Publisher:American Association for Cancer Research
ISSN:0008-5472
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1158/0008-5472.CAN-16-0593
PubMed ID:28209621

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Content: Accepted Version
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Embargo till: 2018-03-01