MAGI1, a New Potential Tumor Suppressor Gene in Estrogen Receptor Positive Breast Cancer

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.

MAGI1 inhibits the AMOTL2/p38 stress pathway and prevents luminal breast tumorigenesis

“…The ERK/MAP Kinase and JNK stress kinase pathways could be influenced by junctions and the forces they sense 15,17,18 . In response to MAGI1 loss, we did not detect any alterations of the main oncogenic pathways: ERK1/2, JNK and Akt pathways (Figure 6A&B) in contrast with recently published results on MAGI1 function 45 . Interestingly, the p38 stress kinase was strongly activated in MCF7 shMAGI1 compared to MCF7 shLuc -: the amount of phosphorylated p38, normalized to total p38 protein level, was increased 2 fold (Figure 6A&B) leading to increased p38 activity as evidenced by the elevated expression of the p38 transcriptional target genes 49 ATF3, SOX9, and GATA6 (SOX2 levels remained unchanged) (Figure 6C).…”

“…S1A). Moreover, public database mining (http://www.kmplot) 44 and recent studies 45 , indicated that low MAGI1 expression levels were associated with worse prognosis in relapse-free survival for BCa patients, but only in ER+ (mainly luminal) molecular BCa subtypes (Kaplan Meier curve; Supplementary Fig. S1B).…”

MAGI1 inhibits the AMOTL2/p38 stress pathway and prevents luminal breast tumorigenesis

“…S1A). Moreover, public database mining ( http://www.kmplot ) 44 and recent studies 45 , indicated that low MAGI1 expression levels were associated with worse prognosis in relapse-free survival for BCa patients, but only in ER+ (mainly luminal) molecular BCa subtypes (Kaplan Meier curve; Supplementary Fig. S1B).…”

Long Non-Coding RNA TMEM220-AS1 Suppressed Hepatocellular Carcinoma by Regulating the miR-484/MAGI1 Axis as a Competing Endogenous RNA

“…The downstream target genes of miR-484 was predicted using MIRDB, MAGI1 with the highest score was chosen to forsubsequentresearch. Some studies indicated that, in estrogen receptor positive breast cancer, MAGI1 is a new potential tumor suppressor gene [29].Via the Wnt/β-Catenin and PTEN/AKT signaling pathways, MAGI1 silencing inhibited apoptosis of glioma cells and promoted the proliferation [30]. Moreover, via regulating PTEN, MAGI1 curbed invasion and migration of HCC [31].Our study con rmed that MAGI1 was the downstream target gene of miR-484, and TMEM220-AS1 released MAGI1 through competitive binding of miR-484, thereby regulating the progression of HCC.…”