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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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.
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.
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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) doi:10.1038/s41388-019-0739-0