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CFP suppresses breast cancer cell growth by TES-mediated upregulation of the transcription factor DDIT3

Oncogene volume 38, pages 4560–4573 (2019)Cite this article

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Abstract

Breast cancer is a heterogeneous genetic disease driven by the accumulation of individual mutations per tumor. Whole-genome sequencing approaches have identified numerous genes with recurrent mutations in primary tumors. Although mutations in well characterized tumor suppressors and oncogenes are overrepresented in these sets, the majority of the genetically altered genes have so far unknown roles in breast cancer progression. To improve the basic understanding of the complex disease breast cancer and to potentially identify novel drug targets or regulators of known cancer-driving pathways, we analyzed 86 wild-type genes and 94 mutated variants for their effect on cell growth using a serially constructed panel of MCF7 cell lines. We demonstrate in subsequent experiments that the metal cation transporter CNNM4 regulates growth by induction of apoptosis and identified a tumor suppressive role of complement factor properdin (CFP) in vitro and in vivo. CFP appears to induce the intracellular upregulation of the pro-apoptotic transcription factor DDIT3 which is associated with endoplasmic reticulum-stress response.

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Acknowledgements

We would like to thank Kerstin Mollenhauer, Anni Schmidt Pedersen and Jette Brandt for their technical assistance. We further thank Bernd Korn for his support in cloning and Guido Posern for support during revision. The work was supported by the Lundbeck Foundation (Grant NanoCAN), and the Rektorspuljen SDU2020 Program (Grant: DAWN-2020); Region Syddanmarks Ph.D.- and Forskningspulje; Fonden Til Lægevidenskabens Fremme; MIO project of the OUH Frontlinjepuljen; Aase og Ejnar Danielsens Fond; Torben og Alice Frimodts Fond, Kong Christian den Tiendes Fond, Brødrene Hartmanns Fond, Fru Astrid Thaysens Legat for Lægevidenskabelig Grundforskning, Grosserer A. V. Lykfeldt og Hustrus Legat, Familien Hede Nielsens Fond, Oda og Hans Svenningsens Fond, Lippmann Fonden and Gangsted Fonden. The work was further support by scholarships granted by Kræftens Bekæmpelse and was co-financed by the INTERREG 4A-program Syddanmark-Schleswig-K.E.R.N. with funds from The European Regional Development Fund. The funding sources had no role in study design, collection of data and analysis, nor in the decision to publish, or preparation of the article.

Author contributions

Conceptualization and methodology, IB, CM, and JM; Investigation, IB, CM, DS, HP, AMJ, SDS, SS, PLH, HC, CC, SBO, MMB, and AR; Formal analysis, ML and MT; Resources, JM, TAK, SWKH, and PK; Writing—original draft, IB and CM; Writing—review & editing, IB, CM, ML, PK, SWKH, HP, PLH, AMJ, and AR; Funding acquisition, IB, CM, ML, SDS, MMB, and JM; Supervision, IB, CM, and JM.

Author information

Author notes

  1. Ines Block

    Present address: Institute for Physiological Chemistry, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany

  2. Carolin Müller

    Present address: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

  3. Henriette Pedersen

    Present address: Brain Tumor Biology Group, Danish Cancer Society Research Center, Copenhagen, Denmark

  4. Markus List

    Present address: Big Data in BioMedicine Group, Chair of Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich, 85354, Freising, Germany

  5. Angela Riedel

    Present address: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany

  6. Angela Riedel

    Present address: Cell Biology and Tumor Biology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany

  7. These authors contributed equally: Ines Block, Carolin Müller

Authors and Affiliations

  1. Lundbeckfonden Center of Excellence NanoCAN, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

    Ines Block, Carolin Müller, Daniel Sdogati, Henriette Pedersen, Markus List, Aleksandra M. Jaskot, Silje Damkjær Syse, Pernille Lund Hansen, Steffen Schmidt, Helle Christiansen, Cinzia Casella, Sidsel Bering Olsen, Monica M. Blomstrøm, Angela Riedel & Jan Mollenhauer

  2. Molecular Oncology, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

    Ines Block, Carolin Müller, Daniel Sdogati, Henriette Pedersen, Markus List, Aleksandra M. Jaskot, Silje Damkjær Syse, Pernille Lund Hansen, Steffen Schmidt, Helle Christiansen, Cinzia Casella, Sidsel Bering Olsen, Monica M. Blomstrøm, Angela Riedel & Jan Mollenhauer

  3. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark

    Ines Block, Mads Thomassen & Torben A. Kruse

  4. Department of Cancer and Inflammation Research, University of Southern Denmark, Odense, Denmark

    Pernille Lund Hansen, Sidsel Bering Olsen & Søren W. Karlskov Hansen

  5. Department of Human Genetics, University of Southern Denmark, Odense, Denmark

    Mads Thomassen & Torben A. Kruse

  6. Department of Biotechnology, Mannheim University of Applied Sciences, Mannheim, Germany

    Petra Kioschis

  7. Brain Tumor Biology Group, Danish Cancer Society Research Center, Copenhagen, Denmark

    Monica M. Blomstrøm

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  1. Ines Block
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GRANT SUPPORT The work was supported by the Lundbeck Foundation (Grant NanoCAN), and the Rektorspuljen SDU2020 Program (Grant: DAWN-2020); Region Syddanmarks Ph.D.- and Forskningspulje; Fonden Til Lægevidenskabens Fremme; MIO project of the OUH Frontlinjepuljen; Aase og Ejnar Danielsens Fond; Torben og Alice Frimodts Fond, Kong Christian den Tiendes Fond, Brødrene Hartmanns Fond, Fru Astrid Thaysens Legat for Lægevidenskabelig Grundforskning, Grosserer A. V. Lykfeldt og Hustrus Legat, Familien Hede Nielsens Fond, Oda og Hans Svenningsens Fond, Lippmann Fonden and Gangsted Fonden. The work was further support by scholarships granted by Kræftens Bekæmpelse and was co-financed by the INTERREG 4A-program Syddanmark-Schleswig-K.E.R.N. with funds from The European Regional Development Fund. The funding sources had no role in study design, collection of data and analysis, nor in the decision to publish, or preparation of the article.

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Block, I., Müller, C., Sdogati, D. et al. CFP suppresses breast cancer cell growth by TES-mediated upregulation of the transcription factor DDIT3. Oncogene 38, 4560–4573 (2019). https://doi.org/10.1038/s41388-019-0739-0

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