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

Oncogene volume 34, pages 681–690 (2015)Cite this article

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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.

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Acknowledgements

We thank Associazione Italiana Ricerca sul Cancro (AIRC) grants IG-10254 (MT) and IG 13431 (RDM) for financial support. We are grateful to Giuseppe Loreto for figure editing, Michele Signore and Mario Falchi for confocal acquisitions.

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Author notes

  1. M Bartucci and R Dattilo: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy

    M Bartucci, R Dattilo, C Moriconi, A Pagliuca, M Patrizii & M Biffoni

  2. Regina Elena National Cancer Institute, Rome, Italy

    M Mottolese, G Federici, A Di Benedetto, F Sperati, M Maugeri-Saccà & R De Maria

  3. Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy

    M Todaro & G Stassi

  4. Department of Surgical Sciences, ‘La Sapienza’ University, Rome, Italy

    M I Amabile

  5. Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, ‘La Sapienza’ University, Rome, Italy

    E Pilozzi

  6. Department of Histology, Microbiology and Medical Biotechnologies, University of Padua School of Medicine, Padua, Italy

    S Piccolo

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  1. M Bartucci
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Correspondence to M Bartucci.

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Bartucci, M., Dattilo, R., Moriconi, C. et al. TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells. Oncogene 34, 681–690 (2015). https://doi.org/10.1038/onc.2014.5

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