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The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation

Nature Structural & Molecular Biology volume 19, pages 220–228 (2012)Cite this article

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Abstract

The splicing-factor oncoprotein SRSF1 (also known as SF2/ASF or ASF/SF2) is upregulated in breast cancers. We investigated the ability of SRSF1 to transform human and mouse mammary epithelial cells in vivo and in vitro. SRSF1-overexpressing COMMA-1D cells formed tumors, following orthotopic transplantation to reconstitute the mammary gland. In three-dimensional (3D) culture, SRSF1-overexpressing MCF-10A cells formed larger acini than control cells, reflecting increased proliferation and delayed apoptosis during acinar morphogenesis. These effects required the first RNA-recognition motif and nuclear functions of SRSF1. SRSF1 overexpression promoted alternative splicing of BIM (also known as BCL2L11) and BIN1 to produce isoforms that lack pro-apoptotic functions and contribute to the phenotype. Finally, SRSF1 cooperated specifically with MYC to transform mammary epithelial cells, in part by potentiating eIF4E activation, and these cooperating oncogenes are significantly coexpressed in human breast tumors. Thus, SRSF1 can promote breast cancer, and SRSF1 itself or its downstream effectors may be valuable targets for the development of therapeutics.

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Figure 1: SRSF1-overexpressing cells form tumors in an orthotopic allograft mouse model.
Figure 2: Overexpression of SRSF1 in MCF-10A cells increases acinar size in an mTOR-dependent manner.
Figure 3: Alternative splicing of target genes in 3D MCF-10A is involved in the SRSF1-induced phenotype.
Figure 4: The SRSF1-induced increase in acinar size requires RRM1 and SRSF1 nuclear functions.
Figure 5: SRSF1 cooperates with MYC but not with ERBB2 or HPV16 E7.
Figure 6: SRSF1 is frequently overexpressed in human breast tumors with elevated MYC.
Figure 7: A model for SRSF1's role in transformation.

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Acknowledgements

We thank M. Egeblad, N. Tonks, V. Aranda and J. Novatt for helpful comments on the manuscript. We thank J. Erby Wilkinson for collaboration and helpful advice with histopathology, and we thank P. Moody for assistance with flow cytometry. This work was supported by grants from the National Cancer Institute (grant CA13106 to A.R.K. and CA098830 to S.K.M.), postdoctoral fellowships from the S.B. Komen Foundation for the Cure (grant KG091029 to O.A.) and from the Fondation pour la Recherche Médicale (grant SPE20070709581 to O.A.), an award grant from the Philippe Foundation to O.A. and an Era of Hope Scholar award from the Department of Defense Breast Cancer Research Program (grant BC075024 to S.K.M.).

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Author notes

  1. Lixing Zhan & Rotem Karni

    Present address: Present addresses: Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Shanghai, China (L.Z.); Department of Biochemistry and Molecular Biology, The Hebrew University Medical School, Jerusalem, Israel (R.K.).,

Authors and Affiliations

  1. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA

    Olga Anczuków, Avi Z Rosenberg, Martin Akerman, Shipra Das, Lixing Zhan, Rotem Karni, Senthil K Muthuswamy & Adrian R Krainer

  2. Graduate Program in Genetics, Stony Brook University, New York, USA

    Avi Z Rosenberg & Shipra Das

  3. Ontario Cancer Institute, Toronto, Ontario, Canada

    Senthil K Muthuswamy

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Contributions

O.A. conducted the experiments. S.D. contributed to the apoptosis assays. M.A. conducted the microarray and statistical analyses. L.Z. contributed to the transplantation experiments. A.Z.R., R.K. and S.K.M. shared protocols and reagents. O.A. and A.R.K. designed the study, analyzed the data and wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Adrian R Krainer.

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Anczuków, O., Rosenberg, A., Akerman, M. et al. The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation. Nat Struct Mol Biol 19, 220–228 (2012). https://doi.org/10.1038/nsmb.2207

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