Chemotherapy resistance frequently drives tumour progression. However, the underlying molecular mechanisms are poorly characterized. Epithelial-to-mesenchymal transition has been shown to correlate with therapy resistance, but the functional link and signalling pathways remain to be elucidated. Here we report that microRNA-30c, a human breast tumour prognostic marker, has a pivotal role in chemoresistance by a direct targeting of the actin-binding protein twinfilin 1, which promotes epithelial-to-mesenchymal transition. An interleukin-6 family member, interleukin-11 is identified as a secondary target of twinfilin 1 in the microRNA-30c signalling pathway. Expression of microRNA-30c inversely correlates with interleukin-11 expression in primary breast tumours and low interleukin-11 correlates with relapse-free survival in breast cancer patients. Our study demonstrates that microRNA-30c is transcriptionally regulated by GATA3 in breast tumours. Identification of a novel microRNA-mediated pathway that regulates chemoresistance in breast cancer will facilitate the development of novel therapeutic strategies.
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Gene Expression Omnibus
We thank Drs Marcus Peter, Suzanne Conzen and Yves Lussier for suggestions and comments on the project and manuscript. We appreciate the experimental support of several core facilities, including animal facility, optical imaging core facility, flow cytometry facility, integrated microscopy core facility, DNA sequencing facility, functional genomics facility and IHC core facility at the University of Chicago. We specifically acknowledge Ryan Duggan, James Cao, David Leclerc, Marianne Greene, Terri Li, Xin Jiang, Shirley Bond, Jaejung Kim, Hui Zheng, Andrew Gusev, Dalong Qian, Yohei Shimono and Ravand Samaeekia for technical help and support. This study was supported in part by The University of Chicago Women’s Board (J.B.), National Institutes of Health (NIH) T90 Regenerative Medicine Training Program DK070103-05, Department of Defense Breast Cancer Research Program W81XWH-09-1-0331, Paul Calabresi K12 Award 1K12CA139160-02, NCI K99 CA160638-01, Chicago Fellows Program at the University of Chicago, and the University of Chicago Clinical and Translational Science Award (UL1 RR024999; H.L.), The University of Chicago Cancer Research Center Pilot Fund, BSD Imaging Research Institute Pilot Research Projects Using Animal Imaging, UCMC/Northshore Collaborative Funds, a Segal Grant and the Virginia and D. K. Ludwig Fund (G.L.G. and H.L.), funds from the Sociedad Española de Oncología Médica (SEOM; A.P.), the Breast SPORE at University of North Carolina 5-P50-CA58223-17 (A.P. and C.M.P.), 1R21CA159066 (D.H.), NIH R21 CA139278 and Pharmacogenetics of Anticancer Agents Research Group UO1GM61393 (M.E.D), NIH Grants U54 CA 126524 and P01 CA139490 (M.F.C.), the Breast Cancer Research Foundation (M.F.C., O.I.O. and C.M.P.), the Breast SPORE P50CA125183-05, the Doris Duke Charitable Foundation (O.I.O and C.N.) and the University of Chicago Cancer Centre Support Grant CA 014599.
SAM analyses of miR-30c regulated genes
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Breast Cancer Research and Treatment (2018)