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dc.contributor.authorDosil Garcia, Maria Alba
dc.contributor.authorMirantes Barbeito, Cristina
dc.contributor.authorEritja Sánchez, Núria
dc.contributor.authorFelip, Isidre
dc.contributor.authorNavaridas Fernández de Bobadilla, Raúl
dc.contributor.authorGatius Calderó, Sònia
dc.contributor.authorSantacana Espasa, Maria
dc.contributor.authorColás, Eva
dc.contributor.authorMoiola, Cristian P.
dc.contributor.authorSchoenenberger, Joan Antoni
dc.contributor.authorEncinas Martín, Mario
dc.contributor.authorGarí Marsol, Eloi
dc.contributor.authorMatias-Guiu, Xavier
dc.contributor.authorDolcet Roca, Xavier
dc.date.accessioned2018-06-12T07:47:35Z
dc.date.available2018-06-12T07:47:35Z
dc.date.issued2017-04-28
dc.identifier.issn0022-3417
dc.identifier.urihttp://hdl.handle.net/10459.1/63495
dc.description.abstractPTEN is one of the most frequently mutated genes in human cancers. The frequency of PTEN alterations is particularly high in endometrial carcinomas. Loss of PTEN leads to dysregulation of cell division, and promotes the accumulation of cell cycle complexes such as cyclin D1-CDK4/6, which is an important feature of the tumour phenotype. Cell cycle proteins have been presented as key targets in the treatment of the pathogenesis of cancer, and several CDK inhibitors have been developed as a strategy to generate new anticancer drugs. Palbociclib (PD-332991) specifically inhibits CDK4/6, and it has been approved for use in metastatic breast cancer in combination with letrazole. Here, we used a tamoxifen-inducible Pten knockout mouse model to assess the antitumour effects of cyclin D1 knockout and CDK4/6 inhibition by palbociclib on endometrial tumours. Interestingly, both cyclin D1 deficiency and palbociclib treatment triggered shrinkage of endometrial neoplasias. In addition, palbociclib treatment significantly increased the survival of Pten-deficient mice, and, as expected, had a general effect in reducing tumour cell proliferation. To further analyse the effects of palbociclib on endometrial carcinoma, we established subcutaneous tumours with human endometrial cancer cell lines and primary endometrial cancer xenografts, which allowed us to provide more translational and predictive data. To date, this is the first preclinical study evaluating the response to CDK4/6 inhibition in endometrial malignancies driven by PTEN deficiency, and it reveals an important role of cyclin D-CDK4/6 activity in their development.
dc.description.sponsorshipThis work was supported by grants FIS PI13/00263, SAF2016-80157-R, PI13/01701, 2009SGR794,Grupos estables AECC (AECC2011), RETICS(RD12/0036/0013), Catalunya contra el cáncer, Programa de intensificación de la investigación, Instituto Carlos III, and BFU 2013-42895-P. MAD holds a predoctoral fellowship from Ministerio de Educación
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherWiley
dc.relationMINECO/PN2013-2016/SAF2016-80157-R
dc.relationMINECO/PN2013-2016/BFU2013-42895-P
dc.relation.isformatofVersió postprint del document publicat a: https://doi.org/10.1002/path.4896
dc.relation.ispartofJournal of Pathology, 2017, vol. 242, núm. 2, p. 152-164
dc.rights(c) Pathological Society of Great Britain and Ireland, 2017
dc.subjectEndometrial carcinoma
dc.subjectPalbociclib
dc.subjectPTEN
dc.titlePalbociclib has antitumour effects on Pten-deficient endometrial neoplasias
dc.title.alternativeInhibition of Cyclin D-CDK4/6 axis in PTEN-deficient neoplasias
dc.typeinfo:eu-repo/semantics/article
dc.date.updated2018-06-12T07:47:38Z
dc.identifier.idgrec025786
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.identifier.doihttps://doi.org/10.1002/path.4896


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