Academic Journal
CIP2A interacts with TopBP1 and drives basal-like breast cancer tumorigenesis
| العنوان: | CIP2A interacts with TopBP1 and drives basal-like breast cancer tumorigenesis |
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| المؤلفون: | Laine, A., Nagelli, S.G., Farrington, C., Butt, U., Cvrljevic, A.N., Vainonen, J.P., Feringa, F.M., Grönroos, 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. |
| المصدر: | Laine , A , Nagelli , S G , Farrington , C , Butt , U , Cvrljevic , A N , Vainonen , J P , Feringa , F M , Grönroos , 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 , .... |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being, name=SDG 3 - Good Health and Well-being |
| الوصف: | © 2021 The Authors; Published by the American Association for Cancer ResearchBasal-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 CIP2Adeficient 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 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | https://research.vu.nl/en/publications/48dc2f34-df5b-49ca-b461-a9acf32b9821 |
| DOI: | 10.1158/0008-5472.CAN-20-3651 |
| الاتاحة: | https://research.vu.nl/en/publications/48dc2f34-df5b-49ca-b461-a9acf32b9821 https://doi.org/10.1158/0008-5472.CAN-20-3651 https://hdl.handle.net/1871.1/48dc2f34-df5b-49ca-b461-a9acf32b9821 |
| Rights: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.8C50FC1F |
| قاعدة البيانات: | BASE |
| DOI: | 10.1158/0008-5472.CAN-20-3651 |
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