TAZ induces growth factor-independent proliferation through activation of EGFR ligand amphiregulin

Yang, Nuo; Morrison, Carl; Liu, Peijun; Miecznikowski, Jeff; Bshara, Wiam; Han, Suxia; Zhu, Qing; Omilian, Angela R.; Li, Xu; Zhang, Jianmin

doi:10.4161/cc.21386

Cited by 91 publications

(78 citation statements)

References 43 publications

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“…We demonstrated that TAZ induces amphiregulin secretion from lung epithelial cells. Our results were consistent with a previous report that TAZ increased amphiregulin production in mammary epithelial cells (49). Epiregulin and neuregulin 1 were also among the potential targets found in the microarray screening of A549 cells, as well as MCF10A and SW480 cells, with TAZ knockdown (13,35).…”

Section: Discussionsupporting

confidence: 82%

An Integrative Analysis of the Tumorigenic Role of TAZ in Human Non–Small Cell Lung Cancer

Noguchi

Saito

Horie

et al. 2014

Clinical Cancer Research

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Purpose: TAZ, also known as WWTR1, has recently been suggested as an oncogene in non-small cell lung cancer (NSCLC). We investigated the clinical relevance of TAZ expression and its functional role in NSCLC tumorigenesis.Experimental Design: We characterized TAZ at the DNA (n ¼ 192), mRNA (n ¼ 196), and protein levels (n ¼ 345) in an NSCLC patient cohort. Gene expression analysis was complemented by a meta-analysis of public datasets (n ¼ 1,382). The effects of TAZ on cell proliferation and cell cycle were analyzed in cell cultures and on tumor growth in mice. TAZ-dependent microarray-based expression profiles in NSCLC cells were combined with molecular profiles in human NSCLC tissues for in silico analysis.Results: Higher TAZ mRNA and protein levels were associated with shorter patient survival. Transduction of TAZ enhanced cell proliferation and tumorigenesis in bronchial epithelial cells, whereas TAZ silencing suppressed cell proliferation and induced cell cycle arrest in NSCLC cells. Microarray and cell culture experiments showed that ErbB ligands (amphiregulin, epiregulin, and neuregulin 1) are downstream targets of TAZ. Our in silico analysis revealed a TAZ signature that substantiated the clinical impact of TAZ and confirmed its relationship to the epidermal growth factor receptor signaling pathway.Conclusion: TAZ expression defines a clinically distinct subgroup of patients with NSCLC. ErbB ligands are suggested to mediate the effects of TAZ on lung cancer progression. Our findings emphasize the tumorigenic role of TAZ and may serve as the basis for new treatment strategies.

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Section: Discussionsupporting

confidence: 82%

An Integrative Analysis of the Tumorigenic Role of TAZ in Human Non–Small Cell Lung Cancer

Noguchi

Saito

Horie

et al. 2014

Clinical Cancer Research

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“…We have noted that TAZ can induce growth factors to promote independent proliferation of breast cancer cells through activation of its transcription target EGFR ligand AREG, and expression of TAZ and EGFR is positively correlated with the invasiveness of breast cancer cell lines (12). These observations implicate the potential benefit of TAZ knockdown on EGFR targeted therapy.…”

Section: Discussionmentioning

confidence: 70%

“…In addition, it has been reported that overexpression of TAZ induced the activation of EGFR signaling, and one of the EGFR ligands, amphiregulin (AREG), is a target of TAZ. AREG functions in a non-cell-autonomous manner to mediate EGF-independent growth and malignant behavior of mammary epithelial cells (12). These studies suggest that the high expression of TAZ may be one of the reasons that TNBC was not sensitive to EGFR inhibitors.…”

Section: Introductionmentioning

confidence: 86%

Knockdown of TAZ modifies triple-negative breast cancer cell sensitivity to EGFR inhibitors by regulating YAP expression

et al. 2016

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Abstract. Triple-negative breast cancer (TNBC) constitutes ~10-15% of breast cancer patients and represents an aggressive subtype with poor overall prognosis. TNBC is an important clinical challenge because it does not respond well to endocrine therapy and have a higher rate of early recurrence and distant metastasis following chemotherapy. Although it has been reported that the epidermal growth factor receptor (EGFR) was overexpressed in ~80% of TNBC, anti-EGFR therapy showed limited clinical benefit according to phase II studies. In this study, we first observed that knockdown of the transcriptional coactivator with PDZ-binding domain (TAZ) gene can regulate the sensitivity of TNBC cell lines to EGFR inhibitors (EGFRI) in a cell context-depended manner. Furthermore, in certain breast cancer cell lines the YES-associated protein, paralog of TAZ (YAP) expression can be upregulated by TAZ inhibition which leads to EGFRI resistance. These results suggest a specific inhibitor to TAZ/YAP combined with anti-EGFR therapy may prove effective and provide a reason why targeting EGFR showed limited clinical benefit in TNBC treatment.

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“…The enrichment of such genes may reflect important non-cell autonomous alterations that are regulated by TAZ/YAP⅐TEAD and TGF␤ signals. Such signals are important for the pro-tumorigenic activity of TAZ and YAP (65,66), and thus we propose that cross-talk between TAZ/YAP⅐TEAD and TGF␤ signals demarcate a distinct local cellular environment that may promote a tumor-initiating niche. The well documented TAZ/YAP⅐TEAD target CTGF best highlights a secreted factor that is cooperatively induced by TGF␤.…”

Section: Discussionmentioning

confidence: 99%

The Transcriptional Regulators TAZ and YAP Direct Transforming Growth Factor β-induced Tumorigenic Phenotypes in Breast Cancer Cells

Hiemer

Szymaniak

Varelas

2014

Journal of Biological Chemistry

201

172

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Background:The TGF␤ and Hippo pathways are dysregulated in metastatic breast cancers. Results: TGF␤-induced cues and nuclear TAZ/YAP converge at the transcriptional level to control gene expression important for tumorigenesis. Conclusion: TAZ/YAP are required to promote TGF␤-induced tumorigenic phenotypes in breast cancer cells. Significance: Our study reveals novel cross-talk between the TGF␤ pathway and TAZ/YAP in late-stage breast cancers.

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TAZ induces growth factor-independent proliferation through activation of EGFR ligand amphiregulin

Cited by 91 publications

References 43 publications

An Integrative Analysis of the Tumorigenic Role of TAZ in Human Non–Small Cell Lung Cancer

An Integrative Analysis of the Tumorigenic Role of TAZ in Human Non–Small Cell Lung Cancer

Knockdown of TAZ modifies triple-negative breast cancer cell sensitivity to EGFR inhibitors by regulating YAP expression

The Transcriptional Regulators TAZ and YAP Direct Transforming Growth Factor β-induced Tumorigenic Phenotypes in Breast Cancer Cells

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