Lung metastasis genes couple breast tumor size and metastatic spread

Andy J. Minn, Gaorav P. Gupta, David Padua, Paula Bos, Don X. Nguyen, Dimitry Nuyten, Bas Kreike, Yi Zhang, Yixin Wang, Hemant Ishwaran, John A. Foekens, Marc Van De Vijver, Joan Massagué

Research output: Contribution to journalArticle

267 Scopus citations

Abstract

The association between large tumor size and metastatic risk in a majority of clinical cancers has led to questions as to whether these observations are causally related or whether one is simply a marker for the other. This is partly due to an uncertainty about how metastasis-promoting gene expression changes can arise in primary tumors. We investigated this question through the analysis of a previously defined "lung metastasis gene-expression signature" (LMS) that mediates experimental breast cancer metastasis selectively to the lung and is expressed by primary human breast cancer with a high risk for developing lung metastasis. Experimentally, we demonstrate that the LMS promotes primary tumor growth that enriches for LMS+ cells, and it allows for intravasation after reaching a critical tumor size. Clinically, this corresponds to LMS+ tumors being larger at diagnosis compared with LMS- tumors and to a marked rise in the incidence of metastasis after LMS+ tumors reach 2 cm. Patients with LMS-expressing primary tumors selectively fail in the lung compared with the bone or other visceral sites and have a worse overall survival. The mechanistic linkage between metastasis gene expression, accelerated tumor growth, and likelihood of metastatic recurrence provided by the LMS may help to explain observations of prognostic gene signatures in primary cancer and how tumor growth can both lead to metastasis and be a marker for cells destined to metastasize.

Original languageEnglish (US)
Pages (from-to)6740-6745
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number16
DOIs
StatePublished - Apr 17 2007
Externally publishedYes

Keywords

  • Cancer
  • Genomics
  • Oncogenesis

ASJC Scopus subject areas

  • Genetics
  • General

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  • Cite this

    Minn, A. J., Gupta, G. P., Padua, D., Bos, P., Nguyen, D. X., Nuyten, D., Kreike, B., Zhang, Y., Wang, Y., Ishwaran, H., Foekens, J. A., Van De Vijver, M., & Massagué, J. (2007). Lung metastasis genes couple breast tumor size and metastatic spread. Proceedings of the National Academy of Sciences of the United States of America, 104(16), 6740-6745. https://doi.org/10.1073/pnas.0701138104