Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, District of Columbia 20037, USA.
Cancer Res. 2010 Aug 15;70(16):6598-608. doi: 10.1158/0008-5472.CAN-10-0907.
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.
尽管 Wnt1 下游信号成分以及细胞质中转移性肿瘤抗原 1 短型 (MTA1s) 的水平在人类乳腺癌中升高，但这两种途径之间是否存在调节交叉对话尚不清楚。在这里，我们提供了证据表明，MTA1s 的水平与 Wnt1 信号成分的刺激之间存在显著相关性，导致在小鼠乳腺上皮细胞和人乳腺癌细胞中，β-连环蛋白的稳定性增加和 Wnt1 靶基因的刺激。我们发现 MTA1s 通过细胞外信号调节激酶 (ERK) 信号影响 Wnt1 途径，因为选择性沉默内源性 MTA1s 或 ERK，或其靶糖原合酶激酶 3β，导致β-连环蛋白表达大量减少，从而抑制 Wnt1 靶基因。此外，在 MTA1s 水平升高的细胞中下调β-连环蛋白，伴随着 Wnt1 靶基因的表达相应下降，确立了 ERK/糖原合酶激酶 3β/β-连环蛋白途径在 MTA1s 刺激乳腺上皮细胞中 Wnt1 靶基因中的机制作用。此外，MTA1s 转基因小鼠的乳腺模拟了 Wnt1 转基因小鼠中发现的表型变化，并表现出 Wnt1 信号通路的整体过度激活，导致β-连环蛋白的稳定性和核积累增加。MTA1s-TG 小鼠的乳腺表现出导管增生和导管原位癌，并且可触及肿瘤的发生率较低。这些发现揭示了 MTA1s 作为乳腺上皮细胞和癌细胞中 Wnt1 信号的重要调节剂的先前未被认识的作用。
