Loss of p27kip1 increases genomic instability and induces radio-resistance in luminal breast cancer cells

Abstract Genomic instability represents a typical feature of aggressive cancers. Normal cells have evolved intricate responses to preserve genomic integrity in response to stress, such as DNA damage induced by γ-irradiation. Cyclin-dependent kinases (CDKs) take crucial part to these safeguard mechan...

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Autores principales:	Stefania Berton, Martina Cusan, Ilenia Segatto, Francesca Citron, Sara D’Andrea, Sara Benevol, Michele Avanzo, Alessandra Dall’Acqua, Monica Schiappacassi, Robert G. Bristow, Barbara Belletti, Gustavo Baldassarre
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/47a79c5a3bde4c8fbdb773c1e4abc039
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spelling	oai:doaj.org-article:47a79c5a3bde4c8fbdb773c1e4abc0392021-12-02T12:32:19ZLoss of p27kip1 increases genomic instability and induces radio-resistance in luminal breast cancer cells10.1038/s41598-017-00734-32045-2322https://doaj.org/article/47a79c5a3bde4c8fbdb773c1e4abc0392017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00734-3https://doaj.org/toc/2045-2322Abstract Genomic instability represents a typical feature of aggressive cancers. Normal cells have evolved intricate responses to preserve genomic integrity in response to stress, such as DNA damage induced by γ-irradiation. Cyclin-dependent kinases (CDKs) take crucial part to these safeguard mechanisms, but involvement of CDK-inhibitors, such as p27Kip1, is less clear. We generated immortalized fibroblasts from p27kip1 knock-out (KO) mouse embryos and re-expressed p27kip1 WT, or its mutant forms, to identify the function of different domains. We γ-irradiated fibroblasts and observed that loss of p27Kip1 was associated to accumulation of residual DNA damage, increased number of mitotic aberration and, eventually, to survival advantage. Nuclear localization and cyclin/CDK-binding of p27Kip1 were critical to mediate proper response to DNA damage. In human luminal breast cancer (LBC) p27kip1 is frequently down-modulated and CDKN1B, p27Kip1 gene, sporadically mutated. We recapitulated results obtained in mouse fibroblasts in a LBC cell line genetically manipulated to be KO for CDKN1B gene. Following γ-irradiation, we confirmed that p27kip1 expression was necessary to preserve genomic integrity and to recognize and clear-out aberrant cells. Our study provides important insights into mechanisms underlying radio-resistance and unveils the possibility for novel treatment options exploiting DNA repair defects in LBC.Stefania BertonMartina CusanIlenia SegattoFrancesca CitronSara D’AndreaSara BenevolMichele AvanzoAlessandra Dall’AcquaMonica SchiappacassiRobert G. BristowBarbara BellettiGustavo BaldassarreNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Stefania Berton Martina Cusan Ilenia Segatto Francesca Citron Sara D’Andrea Sara Benevol Michele Avanzo Alessandra Dall’Acqua Monica Schiappacassi Robert G. Bristow Barbara Belletti Gustavo Baldassarre Loss of p27kip1 increases genomic instability and induces radio-resistance in luminal breast cancer cells
description	Abstract Genomic instability represents a typical feature of aggressive cancers. Normal cells have evolved intricate responses to preserve genomic integrity in response to stress, such as DNA damage induced by γ-irradiation. Cyclin-dependent kinases (CDKs) take crucial part to these safeguard mechanisms, but involvement of CDK-inhibitors, such as p27Kip1, is less clear. We generated immortalized fibroblasts from p27kip1 knock-out (KO) mouse embryos and re-expressed p27kip1 WT, or its mutant forms, to identify the function of different domains. We γ-irradiated fibroblasts and observed that loss of p27Kip1 was associated to accumulation of residual DNA damage, increased number of mitotic aberration and, eventually, to survival advantage. Nuclear localization and cyclin/CDK-binding of p27Kip1 were critical to mediate proper response to DNA damage. In human luminal breast cancer (LBC) p27kip1 is frequently down-modulated and CDKN1B, p27Kip1 gene, sporadically mutated. We recapitulated results obtained in mouse fibroblasts in a LBC cell line genetically manipulated to be KO for CDKN1B gene. Following γ-irradiation, we confirmed that p27kip1 expression was necessary to preserve genomic integrity and to recognize and clear-out aberrant cells. Our study provides important insights into mechanisms underlying radio-resistance and unveils the possibility for novel treatment options exploiting DNA repair defects in LBC.
format	article
author	Stefania Berton Martina Cusan Ilenia Segatto Francesca Citron Sara D’Andrea Sara Benevol Michele Avanzo Alessandra Dall’Acqua Monica Schiappacassi Robert G. Bristow Barbara Belletti Gustavo Baldassarre
author_facet	Stefania Berton Martina Cusan Ilenia Segatto Francesca Citron Sara D’Andrea Sara Benevol Michele Avanzo Alessandra Dall’Acqua Monica Schiappacassi Robert G. Bristow Barbara Belletti Gustavo Baldassarre
author_sort	Stefania Berton
title	Loss of p27kip1 increases genomic instability and induces radio-resistance in luminal breast cancer cells
title_short	Loss of p27kip1 increases genomic instability and induces radio-resistance in luminal breast cancer cells
title_full	Loss of p27kip1 increases genomic instability and induces radio-resistance in luminal breast cancer cells
title_fullStr	Loss of p27kip1 increases genomic instability and induces radio-resistance in luminal breast cancer cells
title_full_unstemmed	Loss of p27kip1 increases genomic instability and induces radio-resistance in luminal breast cancer cells
title_sort	loss of p27kip1 increases genomic instability and induces radio-resistance in luminal breast cancer cells
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/47a79c5a3bde4c8fbdb773c1e4abc039
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Loss of p27kip1 increases genomic instability and induces radio-resistance in luminal breast cancer cells

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