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Published on: November 5, 2021
The Gαh-PLCδ1 signaling axis drives metastatic progression in triple-negative breast cancer
Shang-Pen Huang1, Pei-Yao Liu1, Chih-Jung Kuo2
1Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, 110, Taipei, Taiwan.
Background:
Distant metastasis of triple-negative breast cancer (TNBC) to other organs, e.g., the lungs, has been correlated with poor survival rates among breast cancer patients. Therefore, the identification of useful therapeutic targets to prevent metastasis or even inhibit tumor growth of TNBC is urgently needed. Gαh is a novel GTP-binding protein and known as an inactive form of calcium-dependent tissue transglutaminase. However, the functional consequences of transamidating and G-protein activities of tissue transglutaminase in promoting cancer metastasis are still controversial.
Methods:
Kaplan-Meier analyses were performed to estimate the prognostic values of Gαh and PLCδ1 by utilizing public databases and performing immunohistochemical staining experiments. Cell-based invasion assays and in vivo lung colony-forming and orthotropic lung metastasis models were established to evaluate the effectiveness of interrupting the protein-protein interaction (PPI) between Gαh and PLCδ1 in inhibiting the invasive ability and metastatic potential of TNBC cells.
Results:
Here, we showed that the increased level of cytosolic, not extracellular, Gαh is a poor prognostic marker in breast cancer patients and correlates with the metastatic evolution of TNBC cells. Moreover, clinicopathological analyses revealed that the combined signature of high Gαh/PLCδ1 levels indicates worse prognosis in patients with breast cancer and correlates with lymph node metastasis of ER-negative breast cancer. Blocking the PPI of the Gαh/PLCδ1 complex by synthetically myristoylated PLCδ1 peptide corresponding to the Gαh-binding interface appeared to significantly suppress cellular invasiveness in vitro and inhibit lung metastatic colonies of TNBC cells in vivo.
Conclusions:
This study establishes Gαh/PLCδ1 as a poor prognostic factor for patients with estrogen receptor-negative breast cancers, including TNBCs, and provides therapeutic value by targeting the PPI of the Gαh/PLCδ1 complex to combat the metastatic progression of TNBCs.
Insights
Increased cytosolic Gαh is a poor prognostic marker for triple-negative breast cancer (TNBC) patients. Targeting the Gαh/PLCδ1 interaction inhibits TNBC metastasis, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Distant metastasis in triple-negative breast cancer (TNBC) significantly reduces patient survival.
- Identifying therapeutic targets to inhibit TNBC metastasis and tumor growth is crucial.
- The role of Gαh, an inactive form of tissue transglutaminase, in cancer metastasis is not fully understood.
Purpose of the Study:
- To investigate the prognostic value of Gαh and PLCδ1 in breast cancer.
- To evaluate the potential of targeting the Gαh/PLCδ1 protein-protein interaction (PPI) to inhibit TNBC metastasis.
Main Methods:
- Kaplan-Meier analyses and immunohistochemical staining were used to assess prognostic values.
- In vitro invasion assays and in vivo metastasis models were employed to test therapeutic strategies.
- Synthetic peptides targeting the Gαh/PLCδ1 PPI were utilized.
Main Results:
- Elevated cytosolic Gαh levels correlate with poor prognosis and TNBC metastatic evolution.
- Combined high Gαh/PLCδ1 levels indicate worse prognosis and lymph node metastasis in ER-negative breast cancer.
- Blocking the Gαh/PLCδ1 PPI suppressed cellular invasiveness and lung metastasis in vivo.
Conclusions:
- Gαh/PLCδ1 serves as a poor prognostic factor for estrogen receptor-negative breast cancers, including TNBC.
- Targeting the Gαh/PLCδ1 PPI presents a promising therapeutic approach to combat TNBC metastatic progression.
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