© 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.
| Original language | English |
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| Pages (from-to) | 4319-4331 |
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| Journal | Cancer Research |
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| Volume | 81 |
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| Issue number | 16 |
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| DOIs | |
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| Publication status | Published - 15 Aug 2021 |
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The authors thank Taina Kalevo-Mattila for excellent technical assistance. Erica Nyman is thanked for help in IHC analysis. Professor Wojciech Niedzwiedz and Dr. Andrew Blackford are thanked for sharing research tools and protocols. The authors are very grateful to Ruth Keri Laboratory from Case Western Reserve University for sharing the PDX model. Dr. Michael Ohlmeyer (Atux Iskay LLC) is acknowledged for DBK-1154 and DBK-1160. Johanna Ivaska and Dipanjan Chowdhury are acknowledged for their valuable comments to the data. We acknowledge Finnish Functional Genomics Center, Cell Imaging and Cytometry core facility, and Genome Editing Core at Turku Bioscience Center, and Turku Center for Disease Modeling (TCDM) all supported by Biocenter Finland, and/or ELIXIR Finland. The Central Laboratory Animal Facilities of University of Turku are acknowledged for help with the mouse models. The project was funded by Academy of Finland (323096 to E. Peuhu; 296801, 314443, and 310561 to L.L. Elo), W81XWH-19-BCRP-BTA12 DOD (to G. Narla and J. Westermarck), Finnish Cancer Foundations (to J. Westermarck), Finnish Cultural Foundation (to L.L. Elo), Sigrid Juselius Foundation (to J. Westermarck and E. Peuhu), Breast Cancer Now (2017NovPCC1067 to J. Westermarck and K. Wennerberg), and Governmental Research Funding for Turku University Hospital (to T.J. Gronroos). D.C. Connolly is supported by the Fox Chase Cancer Center FCCC Core grant NCI P30 CA006927. G. Narla is supported by R01 CA181654, HL144741, CA240993, and Rogel Cancer Gift Funds. J. Maurer is supported by Deutsche Forschungsgemeinschaft [DFG, German Research Foundation; PN (407869199)]. A. Laine was supported by Oncode Institute, Svenska Kulturfonden, Orion Research Foundation, Relander Foundation, Inkeri and Mauri V€ansk€a’s Foundation, Finnish Cultural Foundation’s Varsinais-Suomi Regional Fund, and by K. Albin Johanssons Stiftelse. S.G. Nagelli was supported by the University of Turku Graduate School (UTUGS), Instrumentarium Science Foundation, and Ida Montin Foundation.
The authors thank Taina Kalevo-Mattila for excellent technical assistance. Erica Nyman is thanked for help in IHC analysis. Professor Wojciech Niedzwiedz and Dr. Andrew Blackford are thanked for sharing research tools and protocols. The authors are very grateful to Ruth Keri Laboratory from Case Western Reserve University for sharing the PDX model. Dr. Michael Ohlmeyer (Atux Iskay LLC) is acknowledged for DBK-1154 and DBK-1160. Johanna Ivaska and Dipanjan Chowdhury are acknowledged for their valuable comments to the data. We acknowledge Finnish Functional Genomics Center, Cell Imaging and Cytometry core facility, and Genome Editing Core at Turku Bioscience Center, and Turku Center for Disease Modeling (TCDM) all supported by Biocenter Finland, and/or ELIXIR Finland. The Central Laboratory Animal Facilities of University of Turku are acknowledged for help with the mouse models. The project was funded by Academy of Finland (323096 to E. Peuhu; 296801, 314443, and 310561 to L.L. Elo), W81XWH-19-BCRP-BTA12 DOD (to G. Narla and J. Westermarck), Finnish Cancer Foundations (to J. Westermarck), Finnish Cultural Foundation (to L.L. Elo), Sigrid Juselius Foundation (to J. Westermarck and E. Peuhu), Breast Cancer Now (2017NovPCC1067 to J. Westermarck and K. Wennerberg), and Governmental Research Funding for Turku University Hospital (to T.J. Gr?onroos). D.C. Connolly is supported by the Fox Chase Cancer Center FCCC Core grant NCI P30 CA006927. G. Narla is supported by R01 CA181654, HL144741, CA240993, and Rogel Cancer Gift Funds. J. Maurer is supported by Deutsche Forschungsgemeinschaft [DFG, German Research Foundation; PN (407869199)]. A. Laine was supported by Oncode Institute, Svenska Kulturfonden, Orion Research Foundation, Relander Foundation, Inkeri and Mauri V?ansk?a's Foundation, Finnish Cultural Foundation's Varsinais-Suomi Regional Fund, and by K. Albin Johanssons Stiftelse. S.G. Nagelli was supported by the University of Turku Graduate School (UTUGS), Instrumentarium Science Foundation, and Ida Montin Foundation.
