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Identification of molecular determinants of primary and metastatic tumour re-initiation in breast cancer

Nature Cell Biology volume 17, pages 651664 (2015) | Download Citation

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Abstract

Through in vivo selection of multiple ER-negative human breast cancer populations for enhanced tumour-forming capacity, we have derived subpopulations that generate tumours more efficiently than their parental populations at low cell numbers. Tumorigenic-enriched subpopulations exhibited increased expression of LAMA4, FOXQ1 and NAP1L3—genes that are also expressed at greater levels by independently derived metastatic subpopulations. These genes promote metastatic efficiency. FOXQ1 promotes LAMA4 expression, and LAMA4 enhances clonal expansion following substratum detachment in vitro, tumour re-initiation in multiple organs, and disseminated metastatic cell proliferation and colonization. The promotion of cancer cell proliferation and tumour re-initiation by LAMA4 requires β1-integrin. Increased LAMA4 expression marks the transition of human pre-malignant breast lesions to malignant carcinomas, and tumoral LAMA4 overexpression predicts reduced relapse-free survival in ER-negative patients. Our findings reveal common features that govern primary and metastatic tumour re-initiation and identify a key molecular determinant of these processes.

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Acknowledgements

We are grateful to members of our laboratory for insightful discussion and C. Alarcon, N. Halberg, N. Pencheva and A. Nguyen for providing comments on previous versions of this manuscript. We thank C. Blobel, S. Simon and J. Friedman for intellectual input and helpful suggestions. We thank A. Nguyen and J. M. Loo for assistance with splenic injections. We thank N. Halberg for assistance with tail-vein injections. We thank H. Goodarzi for assistance with statistical analysis. We thank P. Furlow for cloning assistance. We thank C. Zhao of the Rockefeller Genomics Resource Center for assistance with transcriptomic profiling. We thank S. Mazel and members of the Rockefeller Flow Cytometry Resource Center for FACS sorting. J.B.R., D.H. and L.B.N. are members of the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program supported by NIH MSTP grant GM07739. S.F.T. is a DOD Era of Hope Scholar and Collaborative Scholars and Innovators Award recipient and Head of the Elizabeth and Vincent Meyer Laboratory of Systems Cancer Biology.

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  1. Laboratory of Systems Cancer Biology, Rockefeller University, Box 16, 1230 York Avenue New York, New York 10065, USA

    • Jason B. Ross
    • , Doowon Huh
    • , Lisa B. Noble
    •  & Sohail F. Tavazoie

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Contributions

S.F.T. conceived the project and supervised all research. J.B.R. and S.F.T. wrote the manuscript. J.B.R. conducted in vivo selection for tumour re-initiation. J.B.R., D.H. and L.B.N. designed, performed and analysed the experiments.

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The authors declare no competing financial interests.

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Correspondence to Sohail F. Tavazoie.

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https://doi.org/10.1038/ncb3148

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