CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis

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dc.contributor.author Laine, Anni
dc.contributor.author Nagelli, Srikar G.
dc.contributor.author Farrington, Caroline
dc.contributor.author Butt, Umar
dc.contributor.author Cvrljevic, Anna N.
dc.contributor.author Vainonen, Julia P.
dc.contributor.author Feringa, Femke M.
dc.contributor.author Gronroos, Tove J.
dc.contributor.author Gautam, Prson
dc.contributor.author Khan, Sofia
dc.contributor.author Sihto, Harri
dc.contributor.author Qiao, Xi
dc.contributor.author Pavic, Karolina
dc.contributor.author Connolly, Denise C.
dc.contributor.author Kronqvist, Pauliina
dc.contributor.author Elo, Laura L.
dc.contributor.author Maurer, Jochen
dc.contributor.author Wennerberg, Krister
dc.contributor.author Medema, Rene H.
dc.contributor.author Joensuu, Heikki
dc.contributor.author Peuhu, Emilia
dc.contributor.author de Visser, Karin
dc.contributor.author Narla, Goutham
dc.contributor.author Westermarck, Jukka
dc.date.accessioned 2021-10-06T13:56:03Z
dc.date.available 2021-12-18T03:45:40Z
dc.date.issued 2021-08
dc.identifier.citation Laine , A , Nagelli , S G , Farrington , C , Butt , U , Cvrljevic , A N , Vainonen , J P , Feringa , F M , Gronroos , T J , Gautam , P , Khan , S , Sihto , H , Qiao , X , Pavic , K , Connolly , D C , Kronqvist , P , Elo , L L , Maurer , J , Wennerberg , K , Medema , R H , Joensuu , H , Peuhu , E , de Visser , K , Narla , G & Westermarck , J 2021 , ' CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis ' , Cancer Research , vol. 81 , no. 16 , pp. 4319-4331 . https://doi.org/10.1158/0008-5472.CAN-20-3651
dc.identifier.other PURE: 169208138
dc.identifier.other PURE UUID: e33a509b-609c-481c-9b25-9786dd15594e
dc.identifier.other WOS: 000685608800015
dc.identifier.other ORCID: /0000-0003-0281-2507/work/101081157
dc.identifier.uri http://hdl.handle.net/10138/335008
dc.description.abstract Basal-like breast cancers (BLBC) are characterized by defects in homologous recombination (HR), deficient mitotic checkpoint, and high-proliferation activity. Here, we discover CIP2A as a candidate driver of BLBC. CIP2A was essential for DNA damage-induced initiation of mouse BLBC-like mammary tumors and for survival of HR-defective BLBC cells. CIP2A was dispensable for normal mammary gland development and for unperturbed mitosis, but selectively essential for mitotic progression of DNA damaged cells. A direct interaction between CIP2A and a DNA repair scaffold protein TopBP1 was identified, and CIP2A inhibition resulted in enhanced DNA damage-induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. In addition to its role in tumor initiation, and survival of BRCA-deficient cells, CIP2A also drove proliferative MYC and E2F1 signaling in basal-like triple-negative breast cancer (BL-TNBC) cells. Clinically, high CIP2A expression was associated with poor patient prognosis in BL-TNBCs but not in other breast cancer subtypes. Small-molecule reactivators of PP2A (SMAP) inhibited CIP2A transcription, phenocopied the CIP2A-deficient DNA damage response (DDR), and inhibited growth of patient-derived BLBC xenograft. In summary, these results demonstrate that CIP2A directly interacts with TopBP1 and coordinates DNAdamage-induced mitotic checkpoint and proliferation, thereby driving BLBC initiation and progression. SMAPs could serve as a surrogate therapeutic strategy to inhibit the oncogenic activity of CIP2A in BLBCs. Significance: These results identify CIP2A as a nongenetic driver and therapeutic target in basal-like breast cancer that regulates DNA damage-induced G2-M checkpoint and proliferative signaling. en
dc.format.extent 13
dc.language.iso eng
dc.relation.ispartof Cancer Research
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject C-MYC
dc.subject SENSITIVITY
dc.subject ACTIVATION
dc.subject HOMOLOG
dc.subject REVEALS
dc.subject BRCA1
dc.subject YEAST
dc.subject GENE
dc.subject P53
dc.subject 3122 Cancers
dc.title CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis en
dc.type Article
dc.contributor.organization Computational Systems Medicine
dc.contributor.organization Institute for Molecular Medicine Finland
dc.contributor.organization Helsinki Institute of Life Science HiLIFE
dc.contributor.organization HUS Gynecology and Obstetrics
dc.contributor.organization Department of Pathology
dc.contributor.organization Helsinki University Hospital Area
dc.contributor.organization Krister Wennerberg / Principal Investigator
dc.contributor.organization Research Programs Unit
dc.contributor.organization Heikki Joensuu / Principal Investigator
dc.contributor.organization Clinicum
dc.contributor.organization HUS Comprehensive Cancer Center
dc.contributor.organization Department of Oncology
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1158/0008-5472.CAN-20-3651
dc.relation.issn 0008-5472
dc.rights.accesslevel openAccess
dc.type.version acceptedVersion

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