title: A gene expression signature that defines breast cancer metastases.
abstract: The most important predictor of prognosis in breast cancer is lymph node status, yet little is known about molecular changes associated with lymph node metastasis. Here, gene expression analysis was performed on primary breast (PBT) and corresponding metastatic lymph node (MLN) tumors to identify molecular signatures associated with nodal metastasis. RNA was isolated after laser microdissection from frozen PBT and MLN from 20 patients with positive lymph nodes and hybridized to the microarray chips. Differential expression was determined using Mann-Whitney testing; Bonferroni corrected P values of 0.05 and 0.001 were calculated. Results were validated using TaqMan assays. Fifty-one genes were differentially expressed (P < 1 x 10(-5), less than twofold differences) between the PBT and paired MLN; 13 with significantly higher expression in the MLN and 38 in the PBT. qRT-PCR validated the differential expression of 40/51 genes. Of the 40 validated genes, NTS and PAX5 were found to have >100-fold higher expression in MLT while COL11A1, KRT14, MMP13, TAC1 and WNT2 had >100-fold higher expression in PBT. Gene expression differences between PBT and MLN suggests that expression of a unique set of genes is required for successful lymph node colonization. Genes expressed at higher levels in PBT are involved in degradation of the extracellular matrix, enabling cells with metastatic potential to disseminate, while genes expressed at higher levels in metastases are involved in transcription, signal transduction and immune response, providing cells with proliferation and survival advantages. These data improve our understanding of the biological processes involved in successful metastatis and provide new targets to arrest tumor cell dissemination and metastatic colonization.
authors.affiliation: Clinical Breast Care Project, Henry M. Jackson Foundation for the Advancement of Military Medicine, 620 Seventh Street, Windber, PA 15963, USA. r.ellsworth@wriwindber.org
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Ellsworth
authors.forename: Jeff
authors.initials: J
authors.lastname: Seebach
authors.forename: Lori A
authors.initials: LA
authors.lastname: Field
authors.forename: Caroline
authors.initials: C
authors.lastname: Heckman
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kane
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hooke
authors.forename: Brad
authors.initials: B
authors.lastname: Love
authors.forename: Craig D
authors.initials: CD
authors.lastname: Shriver
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger