Metastasis-associated protein 1 short form stimulates Wnt1 pathway in mammary epithelial and cancer cells.
Although Wnt1 downstream signaling components as well as cytoplasmic level of metastatic tumor antigen 1 short form (MTA1s) are elevated in human breast cancer, it remains unknown whether a regulatory cross-talk exists between these two pathways. Here, we provide evidence of a remarkable correlation between the levels of MTA1s and stimulation of the Wnt1 signaling components, leading to increased stabilization of beta-catenin and stimulation of Wnt1 target genes in the murine mammary epithelial and human breast cancer cells. We found that MTA1s influences Wnt1 pathway through extracellular signal-regulated kinase (ERK) signaling as selective silencing of the endogenous MTA1s or ERK, or its target glycogen synthase kinase 3beta resulted in a substantial decrease in beta-catenin expression, leading to the inhibition of Wnt1 target genes. Furthermore, downregulation of beta-catenin in cells with elevated MTA1s level was accompanied by a corresponding decrease in the expression of Wnt1 target genes, establishing a mechanistic role for the ERK/glycogen synthase kinase 3beta/beta-catenin pathway in the stimulation of the Wnt1 target genes by MTA1s in mammary epithelial cells. In addition, mammary glands from the virgin MTA1s transgenic mice mimicked the phenotypic changes found in the Wnt1 transgenic mice and exhibited an overall hyperactivation of the Wnt1 signaling pathway, leading to increased stabilization and nuclear accumulation of beta-catenin. Mammary glands from the virgin MTA1s-TG mice revealed ductal hyperplasia and ductal carcinoma in situ, and low incidence of palpable tumors. These findings reveal a previously unrecognized role for MTA1s as an important modifier of the Wnt1 signaling in mammary epithelial and cancer cells.
Kumar
Rakesh
R
Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, District of Columbia 20037, USA.
Balasenthil
Seetharaman
S
Pakala
Suresh B
SB
Rayala
Suresh K
SK
Sahin
Aysegul A
AA
Ohshiro
Kazufumi
K
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D051155:Wnt1 Protein / Q000378:metabolism*
C089320:MTA1 protein, human; C503336:Mta1 protein, mouse; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051155:Wnt1 Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D006655:Histone Deacetylases