Both TGF-β and the PI3K-AKT signaling pathways are known activators of various intracellular pathways that regulate critical cellular functions, including cancer cell survival and proliferation. The interplay between these two oncogenic pathways plays a major role in promoting the initiation, growth, and progression of tumors, including breast cancers. The molecular underpinning of the inter-relationship between these pathways is, however, not fully understood, as is the role of WAVE3 phosphorylation in the regulation of tumor growth and progression. WAVE3 has been established as a major driver of the invasion–metastasis cascade in breast cancer and other tumors of epithelial origin. WAVE3 phosphorylation downstream of PI3K was also shown to regulate cell migration. Here we show that, in addition to PI3K, WAVE3 tyrosine phosphorylation can also be achieved downstream of TGF-β and EGF and that WAVE3 tyrosine phosphorylation is required for its oncogenic activity. Our in vitro analyses found loss of WAVE3 phosphorylation to significantly inhibit cell migration, as well as tumorsphere growth and invasion. In mouse models for breast cancer, loss of WAVE3 phosphorylation inhibited tumor growth of two aggressive breast cancer cell lines of triple-negative subtype. More importantly, we found that WAVE3 phosphorylation is also required for the activation of PI3K, TGF-β, and EGF signaling and their respective downstream effectors. Therefore, our study identified a novel function for WAVE3 in the regulation of breast cancer development and progression through the modulation of a positive feedback loop between WAVE3 and PI3K-TGF-β-EGF signaling pathways.

TGF-β 和 PI3K-AKT 信号通路都是调节关键细胞功能（包括癌细胞存活和增殖）的各种细胞内通路的已知激活剂。这两种致癌途径之间的相互作用在促进包括乳腺癌在内的肿瘤的发生、生长和进展方面发挥着重要作用。然而，这些通路之间相互关系的分子基础尚不完全清楚，WAVE3 磷酸化在调节肿瘤生长和进展中的作用也是如此。WAVE3 已被确定为乳腺癌和其他上皮起源肿瘤侵袭-转移级联反应的主要驱动因素。PI3K 下游的 WAVE3 磷酸化也显示调节细胞迁移。在这里我们表明，除了 PI3K，WAVE3 酪氨酸磷酸化也可以在 TGF-β 和 EGF 的下游实现，并且 WAVE3 酪氨酸磷酸化是其致癌活性所必需的。我们的体外分析发现 WAVE3 磷酸化的丧失可显着抑制细胞迁移以及肿瘤球的生长和侵袭。在乳腺癌小鼠模型中，WAVE3 磷酸化的缺失抑制了两种三阴性亚型侵袭性乳腺癌细胞系的肿瘤生长。更重要的是，我们发现 WAVE3 磷酸化也是激活 PI3K、TGF-β 和 EGF 信号传导及其各自下游效应器所必需的。因此，我们的研究通过调节 WAVE3 和 PI3K-TGF-β-EGF 信号通路之间的正反馈回路，确定了 WAVE3 在调节乳腺癌发展和进展中的新功能。