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Updated: Dec 6, 2025
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
WAVE3 phosphorylation regulates the interplay between PI3K, TGF-β, and EGF signaling pathways in breast cancer
Wei Wang1, Urna Kansakar1, Vesna Markovic1
1Department of Medicine, Rammelkamp Center for Research, Cleveland, OH, USA.
Abstract:
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.
Insights
WAVE3 phosphorylation, crucial for breast cancer growth, is regulated by PI3K, TGF-β, and EGF signaling. Inhibiting WAVE3 phosphorylation halts tumor progression and metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Transforming Growth Factor-beta (TGF-β) and Phosphatidylinositol 3-kinase-AKT (PI3K-AKT) pathways are key regulators of cell functions, including cancer survival and proliferation.
- Their interplay is critical in tumor initiation, growth, and progression, particularly in breast cancers.
- The precise molecular mechanisms linking these pathways and the role of WAVE3 phosphorylation in tumor progression remain incompletely understood.
Purpose of the Study:
- To investigate the role of WAVE3 phosphorylation in breast cancer development and progression.
- To elucidate the relationship between WAVE3 phosphorylation and the PI3K-AKT, TGF-β, and Epidermal Growth Factor (EGF) signaling pathways.
- To determine if WAVE3 phosphorylation is essential for the oncogenic activity of these signaling pathways.
Main Methods:
- In vitro cell migration, tumorsphere growth, and invasion assays.
- In vivo studies using mouse models of aggressive triple-negative breast cancer.
- Analysis of signaling pathway activation and downstream effectors.
Main Results:
- WAVE3 tyrosine phosphorylation is regulated by PI3K, TGF-β, and EGF signaling and is essential for its oncogenic functions.
- Loss of WAVE3 phosphorylation significantly inhibited breast cancer cell migration, tumorsphere formation, and invasion in vitro.
- In vivo, loss of WAVE3 phosphorylation suppressed tumor growth in aggressive breast cancer mouse models.
- WAVE3 phosphorylation is required for the activation of PI3K, TGF-β, and EGF signaling pathways.
Conclusions:
- WAVE3 phosphorylation plays a critical role in breast cancer progression and metastasis.
- A positive feedback loop exists between WAVE3 and the PI3K, TGF-β, and EGF signaling pathways, regulating breast cancer development.
- Targeting WAVE3 phosphorylation presents a potential therapeutic strategy for breast cancer treatment.
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