Abstract

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.

Original languageEnglish
Article number114
JournalJournal of Hematology and Oncology
Volume10
Issue number1
DOIs
Publication statusPublished - Jun 2 2017

Fingerprint

Triple Negative Breast Neoplasms
Breast Neoplasms
Neoplasm Metastasis
Lung
Proteins
GTP-Binding Proteins
Kaplan-Meier Estimate
Protein Transport
Estrogen Receptors
Neoplasms
Survival Rate
Lymph Nodes
Databases
Staining and Labeling
Calcium
Peptides
Therapeutics
Growth

Keywords

  • Gαh
  • Metastasis
  • PLCδ1
  • Protein-protein interaction
  • Triple-negative breast cancer

ASJC Scopus subject areas

  • Hematology
  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

The Gαh-PLCδ1 signaling axis drives metastatic progression in triple-negative breast cancer. / Huang, Shang Pen; Liu, Pei Yao; Kuo, Chih Jung; Chen, Chi Long; Lee, Wei Jiunn; Tsai, Yu Hui; Lin, Yuan Feng.

In: Journal of Hematology and Oncology, Vol. 10, No. 1, 114, 02.06.2017.

Research output: Contribution to journalArticle

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abstract = "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.",
keywords = "Gαh, Metastasis, PLCδ1, Protein-protein interaction, Triple-negative breast cancer",
author = "Huang, {Shang Pen} and Liu, {Pei Yao} and Kuo, {Chih Jung} and Chen, {Chi Long} and Lee, {Wei Jiunn} and Tsai, {Yu Hui} and Lin, {Yuan Feng}",
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T1 - The Gαh-PLCδ1 signaling axis drives metastatic progression in triple-negative breast cancer

AU - Huang, Shang Pen

AU - Liu, Pei Yao

AU - Kuo, Chih Jung

AU - Chen, Chi Long

AU - Lee, Wei Jiunn

AU - Tsai, Yu Hui

AU - Lin, Yuan Feng

PY - 2017/6/2

Y1 - 2017/6/2

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