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Laine A , Nagelli SG , Farrington C , Butt U , Cvrljevic AN , Vainonen JP , Feringa FM , Grönroos TJ , Gautam P , Khan S , Sihto H , Qiao X , Pavic K , Connolly DC , Kronqvist P , Elo LL , Maurer J , Wennerberg K , Medema RH , Joensuu H , Peuhu E , de Visser K , Narla G , Westermarck J
CIP2A interacts with TopBP1 and drives basal-like breast cancer tumorigenesis
Cancer Res. 2021 Aug 15;81(16) :4319-4331
PMID: 34145035    PMCID: PMC8373817    URL: https://www.ncbi.nlm.nih.gov/pubmed/34145035
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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 homologous recombination defective (HRD) 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 (SMAPs) inhibited CIP2A transcription, phenocopied the CIP2A-deficient DNA damage response (DDR), and inhibit growth of patient-derived BLBC xenograft. In summary, these results demonstrate that CIP2A directly interacts with TopBP1 and coordinates DNA-damage 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.
Notes
1538-7445 Laine, Anni Nagelli, Srikar G Orcid: 0000-0002-8320-234x Farrington, Caroline Orcid: 0000-0003-1746-1113 Butt, Umar Cvrljevic, Anna N Orcid: 0000-0003-2851-8701 Vainonen, Julia P Feringa, Femke M Orcid: 0000-0002-6003-4048 Grönroos, Tove J Orcid: 0000-0003-4468-0805 Gautam, Prson Orcid: 0000-0002-1154-8501 Khan, Sofia Sihto, Harri Orcid: 0000-0001-5265-5509 Qiao, Xi Pavic, Karolina Connolly, Denise C Kronqvist, Pauliina Elo, Laura L Orcid: 0000-0001-5648-4532 Maurer, Jochen Orcid: 0000-0003-3962-3128 Wennerberg, Krister Orcid: 0000-0002-1352-4220 Medema, Rene H Joensuu, Heikki Peuhu, Emilia de Visser, Karin Orcid: 0000-0002-0293-868x Narla, Goutham Westermarck, Jukka Orcid: 0000-0001-7478-3018 Journal Article United States Cancer Res. 2021 Jun 18:canres.3651.2020. doi: 10.1158/0008-5472.CAN-20-3651.