title: Lung metastasis genes couple breast tumor size and metastatic spread.
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.
authors.affiliation: Department of Radiation and Cellular Oncology, Center for Molecular Oncology, and Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Andy J
authors.initials: AJ
authors.lastname: Minn
authors.forename: Gaorav P
authors.initials: GP
authors.lastname: Gupta
authors.forename: David
authors.initials: D
authors.lastname: Padua
authors.forename: Paula
authors.initials: P
authors.lastname: Bos
authors.forename: Don X
authors.initials: DX
authors.lastname: Nguyen
authors.forename: Dimitry
authors.initials: D
authors.lastname: Nuyten
authors.forename: Bas
authors.initials: B
authors.lastname: Kreike
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yixin
authors.initials: Y
authors.lastname: Wang
authors.forename: Hemant
authors.initials: H
authors.lastname: Ishwaran
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.forename: Marc
authors.initials: M
authors.lastname: van de Vijver
authors.forename: Joan
authors.initials: J
authors.lastname: Massagué
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D051379:Mice