Abstract
Membrane-associated guanylate kinase (MAGUK) with inverted domain structure-1 (MAGI1) is an intracellular adaptor protein that stabilizes epithelial junctions consistent with a tumor suppressive function in several cancers of epithelial origin. Here we report, based on experimental results and human breast cancer (BC) patients’ gene expression data, that MAGI1 is highly expressed and acts as tumor suppressor in estrogen receptor (ER)+/HER2− but not in HER2+ or triple negative breast cancer (TNBC). Within the ER+/HER2− subset, high MAGI1 expression associates with ESR1 and luminal genes GATA3 and FOXA1 expression and better prognosis, while low MAGI1 levels correlates with higher histological grade, more aggressive phenotype and worse prognosis. Experimentally, MAGI1 downregulation in the ER+ human BC cells MCF7 impairs ER expression and signaling, promotes cell proliferation, and reduces apoptosis and epithelial differentiation. MAGI1 downregulation in the ER+ murine BC cell line 67NR accelerates primary tumor growth and enhances experimental lung metastasis formation. MAGI1 expression is upregulated by estrogen/ER, downregulated by prostaglandin E2/COX-2axis, and negatively correlates with inflammation in ER+/HER2− BC patients. Taken together, we show that MAGI1 is a new potential tumor suppressor in ER+/HER2− breast cancer with possible prognostic value for the identification of patients at high-risk of relapse within this subset.
Highlights
MAGI1 is a cytoplasmic scaffolding protein present at cell-to-cell contacts [1,2,3]
MAGI1 expression was shown to be downregulated in several cancers, including hepatocellular carcinoma, colorectal, cervical, and gastric cancers [4,5,6,7], but little is known about its expression in breast cancer (BC) and its subtypes
We analyzed METABRIC and TCGA gene expression data sets [34,35] of primary human breast cancers and observed that MAGI1 expression is higher in estrogen receptor (ER)+ /HER2− compared to HER2+ and ER− /HER2− BC subtypes (Figure 1a)
Summary
MAGI1 expression is downregulated during cancer progression and was proposed to act as a tumor suppressor in several cancers, including hepatocellular carcinoma, colorectal, cervical and gastric cancers [4,5,6,7]. MAGI1 interacts with the tumor suppressor PTEN leading to PTEN and E-cadherin stability at cell–cell contacts [8,9,10,11]. Stimulated by these observations we sought to analyze whether MAGI1 may act as a tumor suppressor in breast cancer
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