title: Nuclear TAZ expression associates with the triple-negative phenotype in breast cancer.
abstract: The Hippo signaling pathway, a conserved regulator of organ size, has emerged as an important regulatory pathway in cancer. The final transducer effectors of this pathway in mammals are the oncoproteins TAZ and YAP1, which are transcriptional coactivators of target genes involved in cell proliferation and survival. TAZ has been previously reported to play a role in tumorigenesis in breast cancer, but detailed analyses of the different breast cancer phenotypes have not been conducted thus far. We analyzed TAZ expression by immunohistochemistry in a retrospective series of 640 invasive breast carcinomas, comprising estrogen/progesterone receptor-positive (ER+/PR+), HER2-positive, and triple-negative (TN) tumors. We found a strong association of TAZ nuclear expression with the TN phenotype (60.5% TAZ-positive, P<0.001), which was strengthened when stratified into the basal-like subtype (70.8% TAZ-positive, P<0.001). Moreover, 90% of metaplastic breast carcinomas with morphological epithelial-mesenchymal transition features were TAZ-positive. We also investigated whether amplification or differential DNA methylation of the TAZ-encoding locus could account for the observed enhanced TAZ protein expression in the TN/basal phenotype. Amplification of the TAZ locus was analyzed by fluorescence in situ hybridization in 30 TN tumors, and we found gene amplification in some cases (6.45%). DNA methylation analysis was performed using the Sequenom MassArray MALDI-TOF platform, and we observed similar low methylation levels both in TN (n=25) and ER+/PR+ (n=26) tumors. These results were further confirmed using a panel of breast cancer cell lines and using the TCGA dataset. Finally, patients with strong TAZ expression showed poorer clinical outcomes with respect to both recurrence and overall survival.
authors: Department of Pathology Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Avenida Manuel Siurot S/N, 41013 Seville, Spain Red Temática de Investigación Cooperativa en Cáncer (RETICC RD012/0036/0017), Madrid, Spain Department of Pathology Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Carretera de Colmenar Viejo Km. 9.100, 28034 Madrid, Spain Department of Pathology Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Avenida Manuel Siurot S/N, 41013 Seville, Spain Red Temática de Investigación Cooperativa en Cáncer (RETICC RD012/0036/0017), Madrid, Spain Department of Pathology Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Carretera de Colmenar Viejo Km. 9.100, 28034 Madrid, Spain jose.palacios@salud.madrid.org jdiaz-ibis@us.es.
authors: Juan
authors: J
authors: Díaz-Martín
authors: Department of Pathology Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Avenida Manuel Siurot S/N, 41013 Seville, Spain Red Temática de Investigación Cooperativa en Cáncer (RETICC RD012/0036/0017), Madrid, Spain Department of Pathology Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Carretera de Colmenar Viejo Km. 9.100, 28034 Madrid, Spain.
authors: María Ángeles
authors: MÁ
authors: López-García
authors: Department of Pathology Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Avenida Manuel Siurot S/N, 41013 Seville, Spain Red Temática de Investigación Cooperativa en Cáncer (RETICC RD012/0036/0017), Madrid, Spain Department of Pathology Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Carretera de Colmenar Viejo Km. 9.100, 28034 Madrid, Spain.
authors: Laura
authors: L
authors: Romero-Pérez
authors: Department of Pathology Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Avenida Manuel Siurot S/N, 41013 Seville, Spain Red Temática de Investigación Cooperativa en Cáncer (RETICC RD012/0036/0017), Madrid, Spain Department of Pathology Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Carretera de Colmenar Viejo Km. 9.100, 28034 Madrid, Spain.
authors: María Reina
authors: MR
authors: Atienza-Amores
authors: Department of Pathology Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Avenida Manuel Siurot S/N, 41013 Seville, Spain Red Temática de Investigación Cooperativa en Cáncer (RETICC RD012/0036/0017), Madrid, Spain Department of Pathology Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Carretera de Colmenar Viejo Km. 9.100, 28034 Madrid, Spain.
authors: María Luisa
authors: ML
authors: Pecero
authors: Department of Pathology Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Avenida Manuel Siurot S/N, 41013 Seville, Spain Red Temática de Investigación Cooperativa en Cáncer (RETICC RD012/0036/0017), Madrid, Spain Department of Pathology Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Carretera de Colmenar Viejo Km. 9.100, 28034 Madrid, Spain.
authors: María Ángeles
authors: MÁ
authors: Castilla
authors: Department of Pathology Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Avenida Manuel Siurot S/N, 41013 Seville, Spain Red Temática de Investigación Cooperativa en Cáncer (RETICC RD012/0036/0017), Madrid, Spain Department of Pathology Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Carretera de Colmenar Viejo Km. 9.100, 28034 Madrid, Spain.
authors: Michele
authors: M
authors: Biscuola
authors: Department of Pathology Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Avenida Manuel Siurot S/N, 41013 Seville, Spain Red Temática de Investigación Cooperativa en Cáncer (RETICC RD012/0036/0017), Madrid, Spain Department of Pathology Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Carretera de Colmenar Viejo Km. 9.100, 28034 Madrid, Spain.
authors: Almudena
authors: A
authors: Santón
authors: Department of Pathology Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Avenida Manuel Siurot S/N, 41013 Seville, Spain Red Temática de Investigación Cooperativa en Cáncer (RETICC RD012/0036/0017), Madrid, Spain Department of Pathology Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Carretera de Colmenar Viejo Km. 9.100, 28034 Madrid, Spain jose.palacios@salud.madrid.org jdiaz-ibis@us.es.
authors: José
authors: J
authors: Palacios
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010641:Phenotype; D015398:Signal Transduction; D016019:Survival Analysis; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human
keywords: Hippo signaling; TAZ oncoprotein; epithelial–mesenchymal transition; triple-negative breast cancer