Molecular signatures suggest a major role for stromal cells in development of invasive breast cancer.
BACKGROUND
Breast cancer invasion and metastasis involves both epithelial and stromal changes. Our objective was to delineate the pivotal role stroma plays in invasion by comparing transcriptomes among stromal and epithelial cells in normal tissue and invasive breast cancer.


METHODS
Total RNA was isolated from epithelial and stromal cells that were laser captured from normal breast tissue (n = 5) and invasive breast cancer (n = 28). Gene expression was measured using Affymetrix U133A 2.0 GeneChips. Differential gene expression was evaluated and compared within a model that accounted for cell type (epithelial [E] versus stromal [S]), diagnosis (cancer [C] versus normal [N]) as well as cell type-diagnosis interactions.


RESULTS
Compared to NE, the CE transcriptome was highly enriched with genes in proliferative, motility and ECM ontologies. Differences in CS and NS transcriptomes suggested that the ECM was being remodeled in invasive breast cancer, as genes were over-represented in ECM and proteolytic ontologies. Genes more highly expressed in CS compared to CE were primarily ECM components or were involved in the remodeling of ECM, suggesting that ECM biosynthesis and remodeling were initiated in the tumor stroma.


CONCLUSIONS
Based on identified molecular cross-talk between the two contiguous cell populations, a mechanistic model that spurs invasion is proposed, that shows breast cancer invasion proceeds through the acquisition of a motile phenotype in tumor epithelial cells and a reactive phenotype in cancer associated fibroblasts.
Casey
Theresa
T
Animal Science, University of Vermont, Burlington, VT 05405, USA. ande1218@msu.edu
Bond
Jeffrey
J
Tighe
Scott
S
Hunter
Timothy
T
Lintault
Laura
L
Patel
Osman
O
Eneman
Jonathan
J
Crocker
Abigail
A
White
Jeffrey
J
Tessitore
Joseph
J
Stanley
Mary
M
Harlow
Seth
S
Weaver
Donald
D
Muss
Hyman
H
Plaut
Karen
K
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005109:Extracellular Matrix / Q000235:genetics; D005260:Female; D005347:Fibroblasts; D015870:Gene Expression; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009367:Neoplasm Staging; D010641:Phenotype; D017154:Stromal Cells