Abstract
PTEN (Phosphatase and tensin homolog deleted on chromosome 10) expression in stromal fibroblasts suppresses epithelial mammary tumours, but the underlying molecular mechanisms remain unknown. Using proteomic and expression profiling, we show that Pten loss from mammary stromal fibroblasts activates an oncogenic secretome that orchestrates the transcriptional reprogramming of other cell types in the microenvironment. Downregulation of miR-320 and upregulation of one of its direct targets, ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2) are critical events in Pten-deleted stromal fibroblasts responsible for inducing this oncogenic secretome, which in turn promotes tumour angiogenesis and tumour-cell invasion. Expression of the Pten–miR-320–Ets2-regulated secretome distinguished human normal breast stroma from tumour stroma and robustly correlated with recurrence in breast cancer patients. This work reveals miR-320 as a critical component of the Pten tumour-suppressor axis that acts in stromal fibroblasts to reprogramme the tumour microenvironment and curtail tumour progression.
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Acknowledgements
We thank Kara Batte for technical assistance with the microRNA platform, Rumeysa Biyik for bioinformatics assistance, Abdel-Rasoul Mahmoud for statistical assistance and the Ohio State University Human Tissue Resource Network and the Ohio State University Comprehensive Cancer Center Microarray, Nucleic Acids, Proteomic Shared Facilities for technical assistance. This work was funded by grants from the National Institutes of Health to M.C.O. (R01CA053271, P01CA097189) and to G.L. (R01CA85619, R01HD47470, P01CA097189) and from the Komen Breast Cancer Foundation and Evelyn Simmers Charitable Trust to M.C.O.
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M.C.O. and G.L. designed and supervised this study, analysed data and helped write and edit the manuscript. A.B. and J.G. designed and carried out experiments, collected and analysed data and co-wrote the paper. J.A.W., H.M., R.S., A.J.T. and F.L. assisted technically with experiments, and collected and analysed data. M.O.N. assisted with fluorescent and confocal microscopy and immunohistochemistry. L.Y. and S.A.F. contributed to the statistical analyses of data and writing the manuscript. A.S.M., S.C., M.H., M.P. and T.P. contributed to the analysis and comparison of mouse and human profile data. M.G.P. and C.B.M. contributed to the analysis of microRNA data and writing the manuscript. C.K.M., L.D.Y., R.E.J., G.N. and T.J.R. contributed to the histopathological analysis of human samples and writing the manuscript. S.E.L. and E.A.C. contributed to the data analysis and writing the manuscript.
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Bronisz, A., Godlewski, J., Wallace, J. et al. Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320. Nat Cell Biol 14, 159–167 (2012). https://doi.org/10.1038/ncb2396
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DOI: https://doi.org/10.1038/ncb2396
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