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MMTV-cre;Ccn6 knockout mice develop tumors recapitulating human metaplastic breast carcinomas

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Abstract

Metaplastic breast carcinoma is an aggressive form of invasive breast cancer with histological evidence of epithelial to mesenchymal transition (EMT). However, the defining molecular events are unknown. Here we show that CCN6 (WISP3), a secreted matricellular protein of the CCN (CYR61/CTGF/NOV) family, is significantly downregulated in clinical samples of human spindle cell metaplastic breast carcinoma. We generated a mouse model of mammary epithelial-specific Ccn6 deletion by developing a floxed Ccn6 mouse which was bred with an MMTV-Cre mouse. Ccn6fl/fl;MMTV-Cre mice displayed severe defects in ductal branching and abnormal age-related involution compared to littermate controls. Ccn6fl/fl;MMTV-Cre mice developed invasive high grade mammary carcinomas with bona fide EMT, histologically similar to human metaplastic breast carcinomas. Global gene expression profiling of Ccn6fl/fl mammary carcinomas and comparison of orthologous genes with a human metaplastic carcinoma signature revealed a significant overlap of 87 genes (P=5 × 10−11). Among the shared deregulated genes between mouse and human are important regulators of epithelial morphogenesis including Cdh1, Ck19, Cldn3 and 4, Ddr1, and Wnt10a. These results document a causal role for Ccn6 deletion in the pathogenesis of metaplastic carcinomas with histological and molecular similarities with human disease. We provide a platform to study new targets in the diagnosis and treatment of human metaplastic carcinomas, and a new disease relevant model in which to test new treatment strategies.

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Acknowledgements

This work was supported by the National Institutes of Health (NIH) grant R01CA125577 and R01CA107469 (C.G.K), F30CA196084 (T.A), R25GM086262 (PREP program, C.A-G), and the University of Michigan’s Cancer Center Support grant 5 P30 CA46592. We thank Dr Stephen Weiss for the MMTV-Cre line A mice in FVB background, and members of the Kleer lab for critical review of the manuscript.

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Authors and Affiliations

  1. Department of Pathology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA

    E E Martin, W Huang, T Anwar, C Arellano-Garcia, B Burman, M E Gonzalez & C G Kleer

  2. Medical Scientist Training Program and Molecular and Cellular Pathology Graduate Program, University of Michigan, Ann Arbor, MI, USA

    T Anwar

  3. Post-baccalaureate Research Education Program, University of Michigan, Ann Arbor, MI, USA

    C Arellano-Garcia

  4. Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA

    J-L Guan

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  1. E E Martin
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Correspondence to C G Kleer.

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Martin, E., Huang, W., Anwar, T. et al. MMTV-cre;Ccn6 knockout mice develop tumors recapitulating human metaplastic breast carcinomas. Oncogene 36, 2275–2285 (2017). https://doi.org/10.1038/onc.2016.381

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