TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells

• Published in: Oncogene 2015-02, Vol.34 (6), p.681-690
• Main Authors: Bartucci, M, Dattilo, R, Moriconi, C, Pagliuca, A, Mottolese, M, Federici, G, Benedetto, A Di, Todaro, M, Stassi, G, Sperati, F, Amabile, M I, Pilozzi, E, Patrizii, M, Biffoni, M, Maugeri-Saccà, M, Piccolo, S, De Maria, R
• Format: Article
• Language: English
• Subjects: 631/67/1059/2326; 631/67/1347; 631/67/322; 631/67/71; Animals; Apoptosis; Biomarkers; Biomarkers, Tumor - genetics; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer; Care and treatment; Cell Biology; Cell differentiation; Cell Line, Tumor; Chemoresistance; Chemotherapy; Colonization; Development and progression; Disease-Free Survival; Drug resistance; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Health aspects; Human Genetics; Humans; Internal Medicine; Intracellular Signaling Peptides and Proteins - biosynthesis; Intracellular Signaling Peptides and Proteins - genetics; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Multivariate analysis; Neoplasm Metastasis - genetics; Neoplasm Metastasis - pathology; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - pathology; Neoplastic Stem Cells; Oncology; original-article; Physiological aspects; Stem cells; Therapeutic applications; Transcription Factors; Tumorigenicity; Xenograft Model Antitumor Assays
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.5

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.