title: Loss of p27kip1increases 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 mechanisms, but involvement of CDK-inhibitors, such as p27Kip1, is less clear. We generated immortalized fibroblasts from p27kip1knock-out (KO) mouse embryos and re-expressed p27kip1WT, or its mutant forms, to identify the function of different domains. We γ-irradiated fibroblasts and observed that loss of p27Kip1was associated to accumulation of residual DNA damage, increased number of mitotic aberration and, eventually, to survival advantage. Nuclear localization and cyclin/CDK-binding of p27Kip1were critical to mediate proper response to DNA damage. In human luminal breast cancer (LBC) p27kip1is frequently down-modulated and CDKN1B, p27Kip1gene, 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 p27kip1expression 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.
authors.affiliation: Division of Molecular Oncology, CRO of Aviano, National Cancer Institute, Aviano, 33081, Italy.|Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
authors.forename: Stefania
authors.initials: S
authors.lastname: Berton
authors.affiliation: Division of Molecular Oncology, CRO of Aviano, National Cancer Institute, Aviano, 33081, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Cusan
authors.affiliation: Division of Molecular Oncology, CRO of Aviano, National Cancer Institute, Aviano, 33081, Italy.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Segatto
authors.affiliation: Division of Molecular Oncology, CRO of Aviano, National Cancer Institute, Aviano, 33081, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Citron
authors.affiliation: Division of Molecular Oncology, CRO of Aviano, National Cancer Institute, Aviano, 33081, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: D'Andrea
authors.affiliation: Division of Molecular Oncology, CRO of Aviano, National Cancer Institute, Aviano, 33081, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Benevol
authors.affiliation: Division of Medical Physics, CRO of Aviano, National Cancer Institute, Aviano, 33081, Italy.
authors.forename: Michele
authors.identifier: http://orcid.org/0000-0003-1711-4242
authors.initials: M
authors.lastname: Avanzo
authors.affiliation: Division of Molecular Oncology, CRO of Aviano, National Cancer Institute, Aviano, 33081, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Dall'Acqua
authors.affiliation: Division of Molecular Oncology, CRO of Aviano, National Cancer Institute, Aviano, 33081, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Schiappacassi
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
authors.affiliation: Division of Molecular Oncology, CRO of Aviano, National Cancer Institute, Aviano, 33081, Italy. bbelletti@cro.it.
authors.forename: Barbara
authors.identifier: http://orcid.org/0000-0003-2249-0285
authors.initials: B
authors.lastname: Belletti
authors.affiliation: Division of Molecular Oncology, CRO of Aviano, National Cancer Institute, Aviano, 33081, Italy. gbaldassarre@cro.it.
authors.forename: Gustavo
authors.identifier: http://orcid.org/0000-0002-9750-8825
authors.initials: G
authors.lastname: Baldassarre
mesh_terms: D000818:Animals; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency* / Q000235:genetics; D004249:DNA Damage / Q000528:radiation effects; D005260:Female; D015870:Gene Expression; D055786:Gene Knockout Techniques; D042822:Genomic Instability; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D048629:Micronuclei, Chromosome-Defective; D008938:Mitosis / Q000235:genetics / Q000528:radiation effects; D009154:Mutation; D041681:NIH 3T3 Cells; D011836:Radiation Tolerance / Q000235:genetics*
chemical_list: D050760:Cyclin-Dependent Kinase Inhibitor p27