A gene expression signature associated with metastatic cells in effusions of breast carcinoma patients

Abstract

Malignant effusion in invasive breast carcinoma is associated with poor prognosis. To decipher molecular events leading to metastasis and to identify reliable markers for targeted therapies are of crucial need. Therefore, we have used cDNA microarrays to delineate molecular signatures associated with metastasis and relapse in breast carcinoma effusions. Taking advantage of an immunomagnetic method, we have purified to homogeneity EpCAM-positive cells from 34 malignant effusions. Immunopurified cells represented as much as 10% of the whole cell fraction and their epithelial and carcinoma features were confirmed by immunofluorescence labeling. Gene expression profiles of 19 immunopurified effusion samples, were analyzed using human pan-genomic microarrays, and compared with those of 4 corresponding primary tumors, 8 breast carcinoma effusion-derived cell lines, and 4 healthy mammary tissues. Principal component and multiple clustering analyses of microarray data, clearly identified distinctive molecular portraits corresponding to the 4 categories of specimens. Of uppermost interest, effusion samples were arranged in 2 subsets on the basis of their gene expression patterns. The first subset partly shares a gene expression signature with the different cell lines, and overexpresses CD24, CD44 and epithelial cytokeratins 8,18,19. The second subset overexpresses markers related to aggressive invasive carcinoma (uPA receptor, S100A4, vimentin, CXCR4). These findings demonstrate the importance of using pure cell fractions to accurately decipher in silico gene expression of clinical specimens. Further studies will lead to the identification of genes of oustanding importance to diagnose malignant effusion, predict survival and tailor appropriate therapies to the metastatic effusion disease in breast carcinoma patients. ' 2007 Wiley-Liss, Inc.

Role of the CXCR4/CXCL12 signaling axis in breast cancer metastasis to the brain

“…Chemokines are also of great interest for their role in these processes. For instance, Dupont et al observed that in dedifferentiated, aggressive breast cancer effusion samples, genes encoding for CXCR4 were consistently expressed [4]. This report provides a review of the role of the CXCR4/CXCL12 signaling axis in regulating invasion and metastasis of breast cancer cells to the brain.…”

“…For example, in lung cancer models, certain genes when expressed in breast cancer cells successfully led to the seeding of pulmonary metastases [3]. Collectively termed 'metastasis signature genes', these genes are distinguished from oncogenes that fulfill cellautonomous transforming functions through the course of malignant disease; and from 'metastasis virulence genes', defined as those genes that participate in metastatic colonization, but not in primary tumor development [4]. Key genes (HER2, PI-3K/AKT, COX2, MMP1/2, b-catenin, VEGF ERp5) that mediate breast cancer metastasis and survival in foreign vital organs have been deciphered to collectively facilitate the assembly of new tumor blood vessels, the release of tumor cells into circulation and the breaching of capillaries to form metastases [3,5,6].…”

Epithelial mesenchymal transition traits in human breast cancer cell lines

“…Affymetrix analysis of normal ductal and lobular cells, IDC cells and ILC cells microdissected from cryosections revealed that 7 differentially expressed genes which are involved in epithelialmesenchymal transition, TGF-beta and Wnt signalling (CDH1, EMP1, DDR1, DVL1, KRT5, KRT6, KRT17) could distinguish IDC and ILC [77]. Recently, array profiling of EpCAM-immunopurified breast cancer cells in malignant effusions revealed a subset enriched for mesenchymal markers such as vimentin, S100A4, uPAR and CXCR4 [78]. Evidence of EMT has also been observed downstream of HOXB7 in bone-marrow derived (laser catapulted) breast cancer cells [79].…”

Global Gene Expression Profiling Unveils S100A8/A9 as Candidate Markers in H-Ras-Mediated Human Breast Epithelial Cell Invasion

“…Recent studies of the gene expression profiles between human primary tumors and metastases provided molecular insight into potential biomarkers that are indicative of invasiveness of the disease (1)(2)(3)(4)(5). However, interpretation of comparative analyses of patient tissues are complicated due to difficulties controlling degrees of stromal elements in the tumor samples, differences in the genetic background among patients, tumor heterogeneity within an individual, timing of biopsy in relation to the chemotherapy, and/or radiation therapy, etc.…”