title: TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells.
abstract: Metastatic growth in breast cancer (BC) has been proposed as an exclusive property of cancer stem cells (CSCs). However, formal proof of their identity as cells of origin of recurrences at distant sites and the molecular events that may contribute to tumor cell dissemination and metastasis development are yet to be elucidated. In this study, we analyzed a set of patient-derived breast cancer stem cell (BCSC) lines. We found that in vitro BCSCs exhibit a higher chemoresistance and migratory potential when compared with differentiated, nontumorigenic, breast cancer cells (dBCCs). By developing an in vivo metastatic model simulating the disease of patients with early BC, we observed that BCSCs is the only cell population endowed with metastatic potential. Gene-expression profile studies comparing metastagenic and non-metastagenic cells identified TAZ, a transducer of the Hippo pathway and biomechanical cues, as a central mediator of BCSCs metastatic ability involved in their chemoresistance and tumorigenic potential. Overexpression of TAZ in low-expressing dBCCs induced cell transformation and conferred tumorigenicity and migratory activity. Conversely, loss of TAZ in BCSCs severely impaired metastatic colonization and chemoresistance. In clinical data from 99 BC patients, high expression levels of TAZ were associated with shorter disease-free survival in multivariate analysis, thus indicating that TAZ may represent a novel independent negative prognostic factor. Overall, this study designates TAZ as a novel biomarker and a possible therapeutic target for BC.
authors: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: M
authors: M
authors: Bartucci
authors: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: R
authors: R
authors: Dattilo
authors: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: C
authors: C
authors: Moriconi
authors: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: A
authors: A
authors: Pagliuca
authors: Regina Elena National Cancer Institute, Rome, Italy.
authors: M
authors: M
authors: Mottolese
authors: Regina Elena National Cancer Institute, Rome, Italy.
authors: G
authors: G
authors: Federici
authors: Regina Elena National Cancer Institute, Rome, Italy.
authors: A Di
authors: AD
authors: Benedetto
authors: Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
authors: M
authors: M
authors: Todaro
authors: Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
authors: G
authors: G
authors: Stassi
authors: Regina Elena National Cancer Institute, Rome, Italy.
authors: F
authors: F
authors: Sperati
authors: Department of Surgical Sciences, 'La Sapienza' University, Rome, Italy.
authors: M I
authors: MI
authors: Amabile
authors: Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, 'La Sapienza' University, Rome, Italy.
authors: E
authors: E
authors: Pilozzi
authors: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: M
authors: M
authors: Patrizii
authors: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: M
authors: M
authors: Biffoni
authors: Regina Elena National Cancer Institute, Rome, Italy.
authors: M
authors: M
authors: Maugeri-Saccà
authors: Department of Histology, Microbiology and Medical Biotechnologies, University of Padua School of Medicine, Padua, Italy.
authors: S
authors: S
authors: Piccolo
authors: Regina Elena National Cancer Institute, Rome, Italy.
authors: R
authors: R
authors: De Maria
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D014411:Neoplastic Stem Cells; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D023041:Xenograft Model Antitumor Assays
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