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

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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

Title: CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis
Author: Laine, Anni; Nagelli, Srikar G.; Farrington, Caroline; Butt, Umar; Cvrljevic, Anna N.; Vainonen, Julia P.; Feringa, Femke M.; Gronroos, Tove J.; Gautam, Prson; Khan, Sofia; Sihto, Harri; Qiao, Xi; Pavic, Karolina; Connolly, Denise C.; Kronqvist, Pauliina; Elo, Laura L.; Maurer, Jochen; Wennerberg, Krister; Medema, Rene H.; Joensuu, Heikki; Peuhu, Emilia; de Visser, Karin; Narla, Goutham; Westermarck, Jukka
Contributor: University of Helsinki, Computational Systems Medicine
University of Helsinki, HUS Gynecology and Obstetrics
University of Helsinki, Department of Pathology
University of Helsinki, Krister Wennerberg / Principal Investigator
University of Helsinki, Research Programs Unit
Date: 2021-08
Language: eng
Number of pages: 13
Belongs to series: Cancer Research
ISSN: 0008-5472
URI: http://hdl.handle.net/10138/335008
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.
Subject: C-MYC
SENSITIVITY
ACTIVATION
HOMOLOG
REVEALS
BRCA1
YEAST
GENE
P53
3122 Cancers
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