The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells
Open accessAbstract
Cancer stem cells (CSCs) are proposed to drive tumor initiation and progression. Yet, our understanding of the cellular and molecular mechanisms that underlie CSC properties is limited. Here we show that the activity of TAZ, a transducer of the Hippo pathway, is required to sustain self-renewal and tumor-initiation capacities in breast CSCs. TAZ protein levels and activity are elevated in prospective CSCs and in poorly differentiated human tumors and have prognostic value. Gain of TAZ endows self-renewal capacity to non-CSCs. In epithelial cells, TAZ forms a complex with the cell-polarity determinant Scribble, and loss of Scribble--or induction of the epithelial-mesenchymal transition (EMT)--disrupts the inhibitory association of TAZ with the core Hippo kinases MST and LATS. This study links the CSC concept to the Hippo pathway in breast cancer and reveals a mechanistic basis of the control of Hippo kinases by cell polarity.
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Scribble can coimmunoprecipitate with MST1/2 and LATS1/2, as well as with TAZ.
“Scribble can coimmunoprecipitate with MST1/2 and LATS1/2 (Fly Hpo and Wts, respectively; Fig. 3 D), as well as with TAZ (Cordenonsi et al., 2011), and may be essential for interactions among these proteins.”
From Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation (2019) · cites this paper as Cordenonsi et al., 2011
YAP/TAZ pathway signature genes were markedly enriched in MRTX-849-resistant nodules.
“Importantly, YAP/TAZ pathway signature genes (50) were markedly enriched in resistant nodules”
From Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy (2023) · cites this paper as [50]
TAZ expression is increased in 80% of high-grade breast cancers, which is associated with amplification of the WWTR1 locus encoding TAZ in approximately 10% of breast cancers.
“TAZ expression is increased in 80% of high-grade breast cancers, which is associated with amplification of the WWTR1 locus encoding TAZ in approximately 10% of breast cancers [80]”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [80]
In breast cancer stem cells, the co-activator TAZ promotes breast cancer stem cell self-renewal and tumor-initiation capacity.
“In the case of breast CSCs, the co-activator TAZ (transcriptional activator with PDZ-binding motif) has been shown to promote breast CSC self-renewal and tumor-initiation capacity [80].”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [80]
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The hypoxic tumor microenvironment: A driving force for breast cancer progression
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Comprehensive Molecular Characterization of the Hippo Signaling Pathway in Cancer
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YAP/TAZ Signaling and Resistance to Cancer Therapy
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The extracellular matrix in breast cancer
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Role of YAP/TAZ in cell-matrix adhesion-mediated signalling and mechanotransduction
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Self-citationYAP/TAZ as mechanosensors and mechanotransducers in regulating organ size and tumor growth
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“Accumulating evidence supports the importance of the tumor-suppressive Hippo pathway and its mediator YAP in cancer.(1,3-7,12,23) Here, we demonstrate that overexpression of YAP exerts its tumor-supporting properties partly through TEAD4dependent Jag-1 expression and subsequent activation of the Notch pathway in gastr…”
Cellular Mechanotransduction Relies on Tension-Induced and Chaperone-Assisted Autophagy
Ulbricht, A., Eppler, F. J., Tapia, V. E., van der Ven, P. F. M., Hampe, N., Hersch, N., Vakeel, P., Stadel, D., Haas, A., Saftig, P., et al. (2013) · Current Biology · doi:10.1016/j.cub.2013.01.064 · Cited by 288 · see citing works
A genetic screen identifies an LKB1–MARK signalling axis controlling the Hippo–YAP pathway
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Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis
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Estrogen regulates Hippo signaling via GPER in breast cancer
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Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex
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Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation
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“Scribble: A master scaffold 753 transducer TAZ confers cancer stem cell-related traits on breast cancer cells.”
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ZDHHC7-mediated S-palmitoylation of Scribble regulates cell polarity
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MRTF potentiates TEAD‐YAP transcriptional activity causing metastasis
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A feed forward loop enforces YAP/TAZ signaling during tumorigenesis
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TEAD Inhibition Overcomes YAP1/TAZ-Driven Primary and Acquired Resistance to KRASG12C Inhibitors
Edwards, A. C., Stalnecker, C. A., Jean Morales, A., Taylor, K. E., Klomp, J. E., Klomp, J. A., Waters, A. M., Sudhakar, N., Hallin, J., Tang, T. T., et al. (2023) · Cancer Research · doi:10.1158/0008-5472.can-23-2994 · Cited by 91 · see citing works
Endothelial YAP/TAZ Signaling in Angiogenesis and Tumor Vasculature
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The Hippo Signaling Pathway in Drug Resistance in Cancer
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YAP1 oncogene is a context-specific driver for pancreatic ductal adenocarcinoma
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HIF-1α and TAZ serve as reciprocal co-activators in human breast cancer cells
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Loss of DLG5 promotes breast cancer malignancy by inhibiting the Hippo signaling pathway
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- Authors
- Cordenonsi, M., Zanconato, F., Azzolin, L., Forcato, M., Rosato, A., Frasson, C., Inui, M., Montagner, M., Parenti, A. R., Poletti, A., Daidone, M. G., Dupont, S., Basso, G., Bicciato, S., & Piccolo, S.
- Affiliations
- University of Padua (IT)
- University of Modena and Reggio Emilia (IT)
- Ospedale San Bassiano (IT)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- Corresponding author
- Cordenonsi, Michelangelo
- Piccolo, Stefano
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2011-11
- Volume
- 147
- Issue
- 4
- Pages
- 759-772
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2040430549
- Cited by
- 1,381
- References
- 72
- Citations by year
- 2026: 69 · 2025: 67 · 2024: 92 · 2023: 97 · 2022: 106 · 2021: 98 · 2020: 117 · 2019: 102 · 2018: 132 · 2017: 104 · 2016: 97 · 2015: 114 · 2014: 80 · 2013: 58 · 2012: 45
- FWCI
- 28.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 624 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- China Scholarship Council
- Associazione Italiana per la Ricerca sul Cancro
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- TAZ, Hippo signaling pathway, cancer stem cells, breast cancer, self-renewal, tumor initiation, Scribble, cell polarity, epithelial-mesenchymal transition, MST, LATS, prognostic factors
- MeSH terms
- Acyltransferases, Breast Neoplasms, Female, Humans, Membrane Proteins, Neoplasm Metastasis, Transcription Factors, Neoplastic Stem Cells, Signal Transduction, Cell Polarity, Tumor Suppressor Proteins, Epithelial-Mesenchymal Transition
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