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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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.).