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Genes that mediate breast cancer metastasis to lung

Abstract

By means of in vivo selection, transcriptomic analysis, functional verification and clinical validation, here we identify a set of genes that marks and mediates breast cancer metastasis to the lungs. Some of these genes serve dual functions, providing growth advantages both in the primary tumour and in the lung microenvironment. Others contribute to aggressive growth selectively in the lung. Many encode extracellular proteins and are of previously unknown relevance to cancer metastasis.

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Figure 1: Selection of breast cancer cells metastatic to lung.
Figure 2: Gene-expression signature associated with lung metastasis.
Figure 3: Genes in the expression signature mediate lung metastasis.
Figure 4: Lung metastasis signature in human primary breast tumours.
Figure 5: Breast tumorigenicity and lung metastagenicity partially overlap.

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Acknowledgements

We thank R. Benezra, Y. Kang, C. Hudis, L. Norton, N. Rosen and C. VanPoznak for insights and discussions, and K. Manova and the staff of the Molecular Cytology Core Facility for assistance with immunohistochemistry. A.J.M is a recipient of the Leonard B. Holman Research Pathway fellowship. G.P.G. is supported by an NIH Medical Scientist Training Program grant, a fellowship from the Katherine Beineke Foundation and a Department of Defense Breast Cancer Research Program pre-doctoral traineeship award. J.M. is an Investigator of the Howard Hughes Medical Institute. This research is supported by the W.M. Keck Foundation and an NIH grant to J.M., and a US Army Medical Research grant to W.G.

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Correspondence to Joan Massagué.

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Competing interests

All microarray data have been submitted to the Gene Expression Omnibus (GEO) under accession number GSE2603. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure S1

This figure shows validation of a Rosetta-type poor prognosis gene-expression signature and its uniform expression among MDA-MB-231 cell lines. It also demonstrates that the SCPs fall into distinct groups based on gene expression patterns, and exhibit distinct metastatic tropisms. (PDF 214 kb)

Supplementary Figure S2

Confirmation of protein expression for lung metastasis signature genes used in functional validation. (PDF 107 kb)

Supplementary Figure S3

Validation of combination transgenic parental MDA-MB-231 cell lines transduced with lung metastasis genes. (PDF 114 kb)

Supplementary Figure S4

This figure demonstrates that parental MDA-MB-231 cells overexpressing lung metastasis genes are not enhanced in bone metastatic activity. (PDF 441 kb)

Supplementary Figure S5

In this figure, linear combinations of each of the 54 lung metastasis genes weighted by either its estimated Cox model regression coefficient or a t-statistic derived from comparing its expression between LM2 cell lines with the parental MDA-MB-231 cell lines are used to distinguish patients at high risk of developing lung but not bone metastasis. (PDF 129 kb)

Supplementary Figure S6

This figure identifies a subgroup of primary breast cancers that express the lung metastasis signature in the Rosetta data set using hierarchical clustering. (PDF 2056 kb)

Supplementary Figure S7

This figure demonstrates K-means clustering and comparison to LM2 gene expression centroids for primary breast cancers in the Rosetta data set. These methods are used to identify tumours that express the lung metastasis signature, which is used in class prediction training. (PDF 415 kb)

Supplementary Figure Legends

Descriptions of data presented in Supplementary Figures S1-S7. (DOC 32 kb)

Supplementary Tables

All supplementary tables referenced to in the text are included in this file. They include information on cell lines used in the study, as well as several gene lists that are derived in the course of the work. (DOC 216 kb)

Supplementary Data S1

This file contains a pivot table for the Affymetrix U133A gene expression data for all cell lines used in the study. (XLS 14613 kb)

Supplementary Data S2

This file contains an Affymetrix U133A pivot table for gene expression analysis of primary breast cancers in the MSKCC cohort. (XLS 14369 kb)

Supplementary Data S3

This file contains clinical annotations, gene lists, and results of class assignments and predictions utilized in Figure 4 of the main paper. (XLS 293 kb)

Supplementary Methods S1

Description of additional experimental procedures that was not included in the main text due to constraints on space. (DOC 34 kb)

Supplementary Methods S2

Detailed description of analytical methods used in the paper, including derivation of gene lists and class prediction algorithms. (DOC 102 kb)

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Minn, A., Gupta, G., Siegel, P. et al. Genes that mediate breast cancer metastasis to lung. Nature 436, 518–524 (2005). https://doi.org/10.1038/nature03799

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