CIP2A interacts with TopBP1 and drives basal-like breast cancer tumorigenesis

A. Laine; S.G. Nagelli; C. Farrington; U. Butt; A.N. Cvrljevic; J.P. Vainonen; F.M. Feringa; T.J. Grönroos; P. Gautam; S. Khan; H. Sihto; X. Qiao; K. Pavic; D.C. Connolly; P. Kronqvist; L.L. Elo; J. Maurer; K. Wennerberg; R.H. Medema; H. Joensuu; E. Peuhu; K. de Visser; G. Narla; J. Westermarck

doi:10.1158/0008-5472.CAN-20-3651

CIP2A interacts with TopBP1 and drives basal-like breast cancer tumorigenesis

A. Laine
, S.G. Nagelli
, C. Farrington
, U. Butt
, A.N. Cvrljevic
, J.P. Vainonen
, F.M. Feringa
, T.J. Grönroos
, P. Gautam
, S. Khan
, H. Sihto
, X. Qiao
, K. Pavic
, D.C. Connolly
, P. Kronqvist
, L.L. Elo
, J. Maurer
, K. Wennerberg
, R.H. Medema
, H. Joensuu

E. Peuhu, K. de Visser, G. Narla, J. Westermarck

Research output: Contribution to Journal › Article › Academic › peer-review

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 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
Pages (from-to)	4319-4331
Number of pages	13
Journal	Cancer Research
Volume	81
Issue number	16
Early online date	15 Aug 2021
DOIs	https://doi.org/10.1158/0008-5472.CAN-20-3651
Publication status	Published - 15 Aug 2021

Bibliographical note

Funding

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.

Funders	Funder number
Turun Yliopisto
Turku Center for Disease Modeling
Instrumentariumin Tiedesäätiö
Relander Foundation
Suomen Kulttuurirahasto
Ida Montinin Säätiö
K. Albin Johanssons Stiftelse
Oncode Institute
Orionin Tutkimussäätiö
Rogel Cancer Gift Funds
Inkeri and Mauri V?ansk?a's Foundation
Finnish Cancer Foundations
Biocenter Finland
Governmental Research Funding for Turku University Hospital
U.S. Department of Defense
Svenska Kulturfonden
Inkeri and Mauri V€ansk€a’s Foundation
University of Turku Graduate School
Sigrid Juséliuksen Säätiö
Deutsche Forschungsgemeinschaft	407869199
Academy of Finland	296801, 323096, W81XWH-19-BCRP-BTA12, 310561, 314443
Case Western Reserve University	DBK-1154, DBK-1160
National Cancer Institute	R01CA181654, HL144741, P30CA006927, R01CA240993
Breast Cancer Now	2017NovPCC1067

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1158/0008-5472.CAN-20-3651

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Cite this

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., ... Westermarck, J. (2021). CIP2A interacts with TopBP1 and drives basal-like breast cancer tumorigenesis. Cancer Research, 81(16), 4319-4331. https://doi.org/10.1158/0008-5472.CAN-20-3651

@article{48dc2f34df5b49cab461a9acf32b9821,

title = "CIP2A interacts with TopBP1 and drives basal-like breast cancer tumorigenesis",

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 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.",

author = "A. Laine and S.G. Nagelli and C. Farrington and U. Butt and A.N. Cvrljevic and J.P. Vainonen and F.M. Feringa and T.J. Gr{\"o}nroos and P. Gautam and S. Khan and H. Sihto and X. Qiao and K. Pavic and D.C. Connolly and P. Kronqvist and L.L. Elo and J. Maurer and K. Wennerberg and R.H. Medema and H. Joensuu and E. Peuhu and \{de Visser\}, K. and G. Narla and J. Westermarck",

note = "{\textcopyright} 2021 The Authors; Published by the American Association for Cancer Research.",

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doi = "10.1158/0008-5472.CAN-20-3651",

language = "English",

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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 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

TY - JOUR

T1 - CIP2A interacts with TopBP1 and drives basal-like breast cancer tumorigenesis

AU - Laine, A.

AU - Nagelli, S.G.

AU - Farrington, C.

AU - Butt, U.

AU - Cvrljevic, A.N.

AU - Vainonen, J.P.

AU - Feringa, F.M.

AU - Grönroos, T.J.

AU - Gautam, P.

AU - Khan, S.

AU - Sihto, H.

AU - Qiao, X.

AU - Pavic, K.

AU - Connolly, D.C.

AU - Kronqvist, P.

AU - Elo, L.L.

AU - Maurer, J.

AU - Wennerberg, K.

AU - Medema, R.H.

AU - Joensuu, H.

AU - Peuhu, E.

AU - de Visser, K.

AU - Narla, G.

AU - Westermarck, J.

PY - 2021/8/15

Y1 - 2021/8/15

N2 - 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 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.

AB - 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 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.

U2 - 10.1158/0008-5472.CAN-20-3651

DO - 10.1158/0008-5472.CAN-20-3651

M3 - Article

SN - 0008-5472

VL - 81

SP - 4319

EP - 4331

JO - Cancer Research

JF - Cancer Research

IS - 16

ER -

CIP2A interacts with TopBP1 and drives basal-like breast cancer tumorigenesis

Abstract

Bibliographical note

Funding

UN SDGs

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