The Hippo transducers TAZ and YAP in breast cancer: oncogenic activities and clinical implications

The Hippo signalling is emerging as a tumour suppressor pathway whose function is regulated by an intricate network of intracellular and extracellular cues. Defects in the signal cascade lead to the activation of the Hippo transducers TAZ and YAP. Compelling preclinical evidence showed that TAZ/YAP are often aberrantly engaged in breast cancer (BC), where their hyperactivation culminates into a variety of tumour-promoting functions such as epithelial-to-mesenchymal transition, cancer stem cell generation and therapeutic resistance. Having acquired a more thorough understanding in the biology of TAZ/YAP, and the molecular outputs they elicit, has prompted a first wave of exploratory, clinically-focused analyses aimed at providing initial hints on the prognostic/predictive significance of their expression. In this review, we discuss oncogenic activities linked with TAZ/YAP in BC, and we propose clinical strategies for investigating their role as biomarkers in the clinical setting. Finally, we address the therapeutic potential of TAZ/YAP targeting and the modalities that, in our opinion, should be pursued in order to further study the biological and clinical consequences of their inhibition.

[1]  W. Jung,et al.  Metaplastic carcinoma show different expression pattern of YAP compared to triple-negative breast cancer , 2015, Tumor Biology.

[2]  N. Yang,et al.  Characterization of TAZ domains important for the induction of breast cancer stem cell properties and tumorigenesis , 2015, Cell cycle.

[3]  A. Mercurio,et al.  A laminin 511 matrix is regulated by TAZ and functions as the ligand for the α6Bβ1 integrin to sustain breast cancer stem cells , 2015, Genes & development.

[4]  G. Semenza,et al.  Hypoxia-inducible factor 1 mediates TAZ expression and nuclear localization to induce the breast cancer stem cell phenotype , 2014, Oncotarget.

[5]  Maxime Blijlevens,et al.  Molecular profiling and computational network analysis of TAZ-mediated mammary tumorigenesis identifies actionable therapeutic targets , 2014, Oncotarget.

[6]  S. Dupont,et al.  The biology of YAP/TAZ: hippo signaling and beyond. , 2014, Physiological reviews.

[7]  R. Maria,et al.  The Hippo transducer TAZ as a biomarker of pathological complete response in HER2-positive breast cancer patients treated with trastuzumab-based neoadjuvant therapy , 2014, Oncotarget.

[8]  Giuseppe Basso,et al.  YAP/TAZ Incorporation in the β-Catenin Destruction Complex Orchestrates the Wnt Response , 2014, Cell.

[9]  Shan Jiang,et al.  Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer , 2014, Cell.

[10]  Kang Zhang,et al.  Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. , 2014, Cancer cell.

[11]  Joseph Rosenbluh,et al.  KRAS and YAP1 Converge to Regulate EMT and Tumor Survival , 2014, Cell.

[12]  K. Guan,et al.  The Hippo signaling pathway in stem cell biology and cancer , 2014, EMBO reports.

[13]  W. Jung,et al.  Yes-associated protein (YAP) is differentially expressed in tumor and stroma according to the molecular subtype of breast cancer. , 2014, International journal of clinical and experimental pathology.

[14]  Piyush B. Gupta,et al.  The Hippo transducer TAZ interacts with the SWI/SNF complex to regulate breast epithelial lineage commitment. , 2014, Cell reports.

[15]  A. Rosato,et al.  Metabolic control of YAP and TAZ by the mevalonate pathway , 2014, Nature Cell Biology.

[16]  Xaralabos Varelas,et al.  The Transcriptional Regulators TAZ and YAP Direct Transforming Growth Factor β-induced Tumorigenic Phenotypes in Breast Cancer Cells*♦ , 2014, The Journal of Biological Chemistry.

[17]  M. Biffoni,et al.  CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. , 2014, Cell stem cell.

[18]  Andrew J Ewald,et al.  A temporal requirement for Hippo signaling in mammary gland differentiation, growth, and tumorigenesis , 2014, Genes & development.

[19]  K. Jirström,et al.  Decreased expression of Yes-associated protein is associated with outcome in the luminal A breast cancer subgroup and with an impaired tamoxifen response , 2014, BMC Cancer.

[20]  M. Biffoni,et al.  TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells , 2014, Oncogene.

[21]  Lin Mei,et al.  Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility , 2013, Proceedings of the National Academy of Sciences.

[22]  S. Dedhar,et al.  Inactivation of the Hippo tumour suppressor pathway by integrin-linked kinase , 2013, Nature Communications.

[23]  G. Halder,et al.  The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment , 2013, Nature Reviews Drug Discovery.

[24]  Shalom Madar,et al.  'Cancer associated fibroblasts'--more than meets the eye. , 2013, Trends in molecular medicine.

[25]  P. Maroni,et al.  Hypoxia inducible factor-1 is activated by transcriptional co-activator with PDZ-binding motif (TAZ) versus WWdomain-containing oxidoreductase (WWOX) in hypoxic microenvironment of bone metastasis from breast cancer. , 2013, European journal of cancer.

[26]  J. Mesirov,et al.  β-Catenin-Driven Cancers Require a YAP1 Transcriptional Complex for Survival and Tumorigenesis , 2013, Cell.

[27]  David M. Thomas,et al.  The Hippo pathway and human cancer , 2013, Nature Reviews Cancer.

[28]  Z. Shao,et al.  MicroRNA-200a Promotes Anoikis Resistance and Metastasis by Targeting YAP1 in Human Breast Cancer , 2013, Clinical Cancer Research.

[29]  R. Müller,et al.  The ciliopathy disease protein NPHP9 promotes nuclear delivery and activation of the oncogenic transcriptional regulator TAZ. , 2012, Human molecular genetics.

[30]  Peijing Zhang,et al.  LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker , 2012, Nature Medicine.

[31]  K. Guan,et al.  The YAP and TAZ transcription co-activators: key downstream effectors of the mammalian Hippo pathway. , 2012, Seminars in cell & developmental biology.

[32]  R. Hynes,et al.  The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain , 2012, Proceedings of the National Academy of Sciences.

[33]  N. Yang,et al.  TAZ induces growth factor-independent proliferation through activation of EGFR ligand amphiregulin , 2012, Cell cycle.

[34]  M. Bartucci,et al.  DNA Damage Repair Pathways in Cancer Stem Cells , 2012, Molecular Cancer Therapeutics.

[35]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumors , 2012, Nature.

[36]  Jun O. Liu,et al.  Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. , 2012, Genes & development.

[37]  M. Ellis,et al.  A common language in neoadjuvant breast cancer clinical trials: proposals for standard definitions and endpoints. , 2012, The Lancet. Oncology.

[38]  Q. Ou,et al.  Yes-associated protein promotes tumour development in luminal epithelial derived breast cancer. , 2012, European journal of cancer.

[39]  R. Gelber,et al.  Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial , 2012, The Lancet.

[40]  M. Rezai,et al.  Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. , 2012, The Lancet. Oncology.

[41]  Carlo C. Maley,et al.  Clonal evolution in cancer , 2012, Nature.

[42]  S. Bicciato,et al.  The Hippo Transducer TAZ Confers Cancer Stem Cell-Related Traits on Breast Cancer Cells , 2011, Cell.

[43]  L. Pusztai,et al.  Gene expression profiling in breast cancer: classification, prognostication, and prediction , 2011, The Lancet.

[44]  M. Koch,et al.  Distinct types of tumor-initiating cells form human colon cancer tumors and metastases. , 2011, Cell stem cell.

[45]  Y. Hata,et al.  A cell-based assay to screen stimulators of the Hippo pathway reveals the inhibitory effect of dobutamine on the YAP-dependent gene transcription. , 2011, Journal of biochemistry.

[46]  G. Halder,et al.  Modulating F‐actin organization induces organ growth by affecting the Hippo pathway , 2011, The EMBO journal.

[47]  Nicola Elvassore,et al.  Role of YAP/TAZ in mechanotransduction , 2011, Nature.

[48]  Pedro Gaspar,et al.  Actin-Capping Protein and the Hippo pathway regulate F-actin and tissue growth in Drosophila , 2011, Development.

[49]  P. Vigneri,et al.  Cancer Stem Cells and Chemosensitivity , 2011, Clinical Cancer Research.

[50]  R. Müller,et al.  NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway , 2011, The Journal of cell biology.

[51]  R. De Maria,et al.  Therapeutic Targeting of Cancer Stem Cells , 2011, Front. Oncol..

[52]  R. McLendon,et al.  Acidic stress promotes a glioma stem cell phenotype , 2011, Cell Death and Differentiation.

[53]  Xiaolong Yang,et al.  Taxol resistance in breast cancer cells is mediated by the hippo pathway component TAZ and its downstream transcriptional targets Cyr61 and CTGF. , 2011, Cancer research.

[54]  K. Anderson,et al.  Genetic variegation of clonal architecture and propagating cells in leukaemia , 2011, Nature.

[55]  James R. Downing,et al.  Evolution of human BCR–ABL1 lymphoblastic leukaemia-initiating cells , 2011, Nature.

[56]  M. Todaro,et al.  Tumorigenic and metastatic activity of human thyroid cancer stem cells. , 2010, Cancer research.

[57]  Zhengyu Zha,et al.  The Hippo Tumor Pathway Promotes TAZ Degradation by Phosphorylating a Phosphodegron and Recruiting the SCFβ-TrCP E3 Ligase* , 2010, The Journal of Biological Chemistry.

[58]  N. Cho,et al.  CD24+ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells , 2010, Oncogene.

[59]  Jianmin Zhang,et al.  YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway , 2009, Nature Cell Biology.

[60]  Jeannie T. Lee,et al.  Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. , 2009, Cancer cell.

[61]  Hui Wang,et al.  Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. , 2009, Cancer cell.

[62]  W. Hong,et al.  TEADs Mediate Nuclear Retention of TAZ to Promote Oncogenic Transformation* , 2009, Journal of Biological Chemistry.

[63]  G. Maira,et al.  Distinct pools of cancer stem-like cells coexist within human glioblastomas and display different tumorigenicity and independent genomic evolution , 2009, Oncogene.

[64]  C. Mein,et al.  Yes-associated protein (YAP) functions as a tumor suppressor in breast , 2008, Cell Death and Differentiation.

[65]  Wenjun Guo,et al.  The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells , 2008, Cell.

[66]  Q. Zeng,et al.  A role for TAZ in migration, invasion, and tumorigenesis of breast cancer cells. , 2008, Cancer research.

[67]  B. Wang,et al.  The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control. , 2008, Developmental cell.

[68]  Shian Wu,et al.  The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. , 2008, Developmental cell.

[69]  M. Biffoni,et al.  Identification and expansion of the tumorigenic lung cancer stem cell population , 2008, Cell Death and Differentiation.

[70]  Zhengyu Zha,et al.  TAZ Promotes Cell Proliferation and Epithelial-Mesenchymal Transition and Is Inhibited by the Hippo Pathway , 2008, Molecular and Cellular Biology.

[71]  R. Jaenisch,et al.  YAP1 Increases Organ Size and Expands Undifferentiated Progenitor Cells , 2007, Current Biology.

[72]  Li Li,et al.  Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. , 2007, Genes & development.

[73]  Walter Kolch,et al.  RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein. , 2007, Molecular cell.

[74]  G. Feldmann,et al.  Elucidation of a Universal Size-Control Mechanism in Drosophila and Mammals , 2007, Cell.

[75]  Y. Shaul,et al.  The Yes-associated protein 1 stabilizes p73 by preventing Itch-mediated ubiquitination of p73 , 2007, Cell Death and Differentiation.

[76]  I. Weissman,et al.  Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma , 2007, Proceedings of the National Academy of Sciences.

[77]  L. Ricci-Vitiani,et al.  Identification and expansion of human colon-cancer-initiating cells , 2007, Nature.

[78]  Jianmin Zhang,et al.  Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon , 2006, Proceedings of the National Academy of Sciences.

[79]  N. Maitland,et al.  Prospective identification of tumorigenic prostate cancer stem cells. , 2005, Cancer research.

[80]  P. Dalerba,et al.  Identification of pancreatic cancer stem cells. , 2006, Cancer research.

[81]  Jianbin Huang,et al.  The Hippo Signaling Pathway Coordinately Regulates Cell Proliferation and Apoptosis by Inactivating Yorkie, the Drosophila Homolog of YAP , 2005, Cell.

[82]  G. Blandino,et al.  The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA Damage. , 2005, Molecular cell.

[83]  R. Henkelman,et al.  Identification of human brain tumour initiating cells , 2004, Nature.

[84]  B. Wang,et al.  The Drosophila Ste20 family kinase dMST functions as a tumor suppressor by restricting cell proliferation and promoting apoptosis. , 2003, Genes & development.

[85]  N. Tapon,et al.  The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila , 2003, Nature Cell Biology.

[86]  Ryan S. Udan,et al.  Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway , 2003, Nature Cell Biology.

[87]  Shian Wu,et al.  hippo Encodes a Ste-20 Family Protein Kinase that Restricts Cell Proliferation and Promotes Apoptosis in Conjunction with salvador and warts , 2003, Cell.

[88]  I. Hariharan,et al.  The Drosophila Mst Ortholog, hippo, Restricts Growth and Cell Proliferation and Promotes Apoptosis , 2003, Cell.

[89]  S. Morrison,et al.  Prospective identification of tumorigenic breast cancer cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[90]  D. Haber,et al.  salvador Promotes Both Cell Cycle Exit and Apoptosis in Drosophila and Is Mutated in Human Cancer Cell Lines , 2002, Cell.

[91]  L. Castagnoli,et al.  Physical interaction with Yes-associated protein enhances p73 transcriptional activity. , 2001, The Journal of biological chemistry.

[92]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[93]  J. Dick,et al.  Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell , 1997, Nature Medicine.

[94]  J. Gudmundsson,et al.  Loss of heterozygosity at chromosome 11 in breast cancer: association of prognostic factors with genetic alterations. , 1995, British Journal of Cancer.

[95]  G. Hampton,et al.  Loss of heterozygosity for chromosome 11 in primary human breast tumors is associated with poor survival after metastasis. , 1995, Cancer research.

[96]  T. Xu,et al.  Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. , 1995, Development.

[97]  P J Bryant,et al.  The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. , 1995, Genes & development.

[98]  C. Croce,et al.  Loss of heterozygosity at 11q22-q23 in breast cancer. , 1994, Cancer research.

[99]  G. Hampton,et al.  Loss of heterozygosity in sporadic human breast carcinoma: a common region between 11q22 and 11q23.3. , 1994, Cancer research.

[100]  P. Maroni,et al.  Bone metastatic process of breast cancer involves methylation state affecting E-cadherin expression through TAZ and WWOX nuclear effectors. , 2013, European journal of cancer.

[101]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumours , 2013 .

[102]  Zhongmei Zhou,et al.  TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes breast cell proliferation and tumorigenesis. , 2012, Carcinogenesis.

[103]  Giulia Bianchi,et al.  Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. , 2012, The Lancet. Oncology.

[104]  K. Guan,et al.  A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). , 2010, Genes & development.

[105]  J. Salk.  Clonal evolution in cancer , 2010 .

[106]  G. Melino,et al.  Yes-Associated Protein (YAP) is a critical mediator of c-Jun-dependent apoptosis , 2008, Cell Death and Differentiation.

[107]  G. Halder,et al.  The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis , 2006, Nature Cell Biology.

[108]  J. Downward,et al.  Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. , 2003, Molecular cell.