Chapelle Jennifer, Baudino Annalisa, Torelli Federico, Savino Aurora, Morellato Alessandro, Angelini Costanza, Salemme Vincenzo, Centonze Giorgia, Natalini Dora, Gai Marta, Poli Valeria, Kähne Thilo, Turco Emilia, Defilippi Paola
Department of Molecular Biotechnology and Health Sciences, University of Torino Torino 10126, Italy.
Institute of Experimental Internal Medicine, Medical Faculty, Otto von Guericke University Magdeburg 39120, Germany.
Am J Cancer Res. 2020 Dec 1;10(12):4308-4324. eCollection 2020.
The p140Cap adaptor protein, encoded by the gene, negatively controls tumor progression, as demonstrated in the subgroup of -amplified breast cancers and in neuroblastoma patients, where high p140Cap expression predicts a decreased probability of developing metastasis, with a significantly prolonged survival. In NeuT mice, a preclinical model or Her2-positive breast cancer, we previously reported that p140Cap counteracts Her2-dependent breast cancer progression, associating with the specific Rac1 Guanine Nucleotide Exchange Factor, Tiam1, and limiting the activation of both Tiam1 and Rac1. Here, we show that in TUBO breast cancer cells derived from the NeuT tumors, p140Cap expression causes Tiam1 redistribution along the apicobasal junctional axis. Furthermore, p140Cap and Tiam1 interact with E-cadherin, a member of the adherence junction, with a concomitant increase of E-cadherin at the cell membrane. We characterized biochemically the interaction between p140Cap and Tiam1, showing that the amino terminal region of p140Cap (1-287 amino acids) is sufficient to associate with full length Tiam1, and with the truncated catalytic domain of Tiam1, with a concomitant decrease of the Tiam1 activity. Moreover, in a large cohort of Her2 positive breast cancer, high levels of expression positively correlates with increased survival in patients with high expression. Overall, our findings sustain a protective role of p140Cap in Her2 positive breast cancer, where p140Cap can associate with Tiam1 and negatively regulate the Tiam1/Rac1 axis.
由该基因编码的衔接蛋白p140Cap对肿瘤进展具有负调控作用，这在扩增的乳腺癌亚组和神经母细胞瘤患者中得到了证实，其中p140Cap高表达预示着发生转移的可能性降低，生存期显著延长。在NeuT小鼠（一种Her2阳性乳腺癌的临床前模型）中，我们之前报道p140Cap可对抗Her2依赖性乳腺癌进展，与特异性Rac1鸟嘌呤核苷酸交换因子Tiam1相关联，并限制Tiam1和Rac1的激活。在这里，我们表明在源自NeuT肿瘤的TUBO乳腺癌细胞中，p140Cap表达导致Tiam1沿顶-基连接轴重新分布。此外，p140Cap和Tiam1与黏附连接成员E-钙黏蛋白相互作用，同时细胞膜上的E-钙黏蛋白增加。我们对p140Cap和Tiam1之间的相互作用进行了生化表征，表明p140Cap的氨基末端区域（1-287个氨基酸）足以与全长Tiam1以及Tiam1的截短催化结构域结合，同时Tiam1活性降低。此外，在一大群Her2阳性乳腺癌患者中，高水平的表达与高表达患者的生存期延长呈正相关。总体而言，我们的研究结果支持p140Cap在Her2阳性乳腺癌中的保护作用，其中p140Cap可与Tiam1结合并负调控Tiam1/Rac1轴。
