Prolyl‐isomerase Pin1 controls normal and cancer stem cells of the breast
Abstract Mammary epithelial stem cells are fundamental to maintain tissue integrity. Cancer stem cells (CSCs) are implicated in both treatment resistance and disease relapse, and the molecular bases of their malignant properties are still poorly understood. Here we show that both normal stem cells a...
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| Format: | Article |
| Language: | English |
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Springer Nature
2013-12-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.1002/emmm.201302909 |
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| author | Alessandra Rustighi Alessandro Zannini Luca Tiberi Roberta Sommaggio Silvano Piazza Giovanni Sorrentino Simona Nuzzo Antonella Tuscano Vincenzo Eterno Federica Benvenuti Libero Santarpia Iannis Aifantis Antonio Rosato Silvio Bicciato Alberto Zambelli Giannino Del Sal |
| author_facet | Alessandra Rustighi Alessandro Zannini Luca Tiberi Roberta Sommaggio Silvano Piazza Giovanni Sorrentino Simona Nuzzo Antonella Tuscano Vincenzo Eterno Federica Benvenuti Libero Santarpia Iannis Aifantis Antonio Rosato Silvio Bicciato Alberto Zambelli Giannino Del Sal |
| author_sort | Alessandra Rustighi |
| collection | DOAJ |
| description | Abstract Mammary epithelial stem cells are fundamental to maintain tissue integrity. Cancer stem cells (CSCs) are implicated in both treatment resistance and disease relapse, and the molecular bases of their malignant properties are still poorly understood. Here we show that both normal stem cells and CSCs of the breast are controlled by the prolyl‐isomerase Pin1. Mechanistically, following interaction with Pin1, Notch1 and Notch4, key regulators of cell fate, escape from proteasomal degradation by their major ubiquitin‐ligase Fbxw7α. Functionally, we show that Fbxw7α acts as an essential negative regulator of breast CSCs' expansion by restraining Notch activity, but the establishment of a Notch/Pin1 active circuitry opposes this effect, thus promoting breast CSCs self‐renewal, tumor growth and metastasis in vivo. In human breast cancers, despite Fbxw7α expression, high levels of Pin1 sustain Notch signaling, which correlates with poor prognosis. Suppression of Pin1 holds promise in reverting aggressive phenotypes, through CSC exhaustion as well as recovered drug sensitivity carrying relevant implications for therapy of breast cancers. |
| format | Article |
| id | doaj-art-b055e50d978747c590e5ad139df9ce9d |
| institution | OA Journals |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2013-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-b055e50d978747c590e5ad139df9ce9d2025-08-20T02:17:53ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842013-12-01619911910.1002/emmm.201302909Prolyl‐isomerase Pin1 controls normal and cancer stem cells of the breastAlessandra Rustighi0Alessandro Zannini1Luca Tiberi2Roberta Sommaggio3Silvano Piazza4Giovanni Sorrentino5Simona Nuzzo6Antonella Tuscano7Vincenzo Eterno8Federica Benvenuti9Libero Santarpia10Iannis Aifantis11Antonio Rosato12Silvio Bicciato13Alberto Zambelli14Giannino Del Sal15Laboratorio Nazionale CIB (LNCIB), Area Science ParkLaboratorio Nazionale CIB (LNCIB), Area Science ParkLaboratorio Nazionale CIB (LNCIB), Area Science ParkDipartimento di Scienze Oncologiche e Chirurgiche, Università degli Studi di Padova e Istituto Oncologico Veneto IRCCSLaboratorio Nazionale CIB (LNCIB), Area Science ParkLaboratorio Nazionale CIB (LNCIB), Area Science ParkCenter for Genome Research, Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio EmiliaOncology Department IRCCS Fondazione Salvatore MaugeriOncology Department IRCCS Fondazione Salvatore MaugeriInternational Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science ParkTranslational Research Unit, Istituto Toscano TumoriHoward Hughes Medical Institute and Department of Pathology, NYU School of MedicineDipartimento di Scienze Oncologiche e Chirurgiche, Università degli Studi di Padova e Istituto Oncologico Veneto IRCCSCenter for Genome Research, Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio EmiliaOncology Department IRCCS Fondazione Salvatore MaugeriLaboratorio Nazionale CIB (LNCIB), Area Science ParkAbstract Mammary epithelial stem cells are fundamental to maintain tissue integrity. Cancer stem cells (CSCs) are implicated in both treatment resistance and disease relapse, and the molecular bases of their malignant properties are still poorly understood. Here we show that both normal stem cells and CSCs of the breast are controlled by the prolyl‐isomerase Pin1. Mechanistically, following interaction with Pin1, Notch1 and Notch4, key regulators of cell fate, escape from proteasomal degradation by their major ubiquitin‐ligase Fbxw7α. Functionally, we show that Fbxw7α acts as an essential negative regulator of breast CSCs' expansion by restraining Notch activity, but the establishment of a Notch/Pin1 active circuitry opposes this effect, thus promoting breast CSCs self‐renewal, tumor growth and metastasis in vivo. In human breast cancers, despite Fbxw7α expression, high levels of Pin1 sustain Notch signaling, which correlates with poor prognosis. Suppression of Pin1 holds promise in reverting aggressive phenotypes, through CSC exhaustion as well as recovered drug sensitivity carrying relevant implications for therapy of breast cancers.https://doi.org/10.1002/emmm.201302909breast cancerFbxw7 E3 ubiquitin‐ligaseNotchprolyl‐isomerase Pin1stem cells |
| spellingShingle | Alessandra Rustighi Alessandro Zannini Luca Tiberi Roberta Sommaggio Silvano Piazza Giovanni Sorrentino Simona Nuzzo Antonella Tuscano Vincenzo Eterno Federica Benvenuti Libero Santarpia Iannis Aifantis Antonio Rosato Silvio Bicciato Alberto Zambelli Giannino Del Sal Prolyl‐isomerase Pin1 controls normal and cancer stem cells of the breast EMBO Molecular Medicine breast cancer Fbxw7 E3 ubiquitin‐ligase Notch prolyl‐isomerase Pin1 stem cells |
| title | Prolyl‐isomerase Pin1 controls normal and cancer stem cells of the breast |
| title_full | Prolyl‐isomerase Pin1 controls normal and cancer stem cells of the breast |
| title_fullStr | Prolyl‐isomerase Pin1 controls normal and cancer stem cells of the breast |
| title_full_unstemmed | Prolyl‐isomerase Pin1 controls normal and cancer stem cells of the breast |
| title_short | Prolyl‐isomerase Pin1 controls normal and cancer stem cells of the breast |
| title_sort | prolyl isomerase pin1 controls normal and cancer stem cells of the breast |
| topic | breast cancer Fbxw7 E3 ubiquitin‐ligase Notch prolyl‐isomerase Pin1 stem cells |
| url | https://doi.org/10.1002/emmm.201302909 |
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