Gene expression profiling of tumour epithelial and stromal compartments during breast cancer progression.
The progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) marks a critical step in the evolution of breast cancer. There is some evidence to suggest that dynamic interactions between the neoplastic cells and the tumour microenvironment play an important role. Using the whole-genome cDNA-mediated annealing, selection, extension and ligation assay (WG-DASL, Illumina), we performed gene expression profiling on 87 formalin-fixed paraffin-embedded (FFPE) samples from 17 patients consisting of matched IDC, DCIS and three types of stroma: IDC-S (<3 mm from IDC), DCIS-S (<3 mm from DCIS) and breast cancer associated-normal stroma (BC-NS; >10 mm from IDC or DCIS). Differential gene expression analysis was validated by quantitative real time-PCR, immunohistochemistry and immunofluorescence. The expression of several genes was down-regulated in stroma from cancer patients relative to normal stroma from reduction mammoplasties. In contrast, neoplastic epithelium underwent more gene expression changes during progression, including down regulation of SFRP1. In particular, we observed that molecules related to extracellular matrix (ECM) remodelling (e.g. COL11A1, COL5A2 and MMP13) were differentially expressed between DCIS and IDC. COL11A1 was overexpressed in IDC relative to DCIS and was expressed by both the epithelial and stromal compartments but was enriched in invading neoplastic epithelial cells. The contributions of both the epithelial and stromal compartments to the clinically important scenario of progression from DCIS to IDC. Gene expression profiles, we identified differential expression of genes related to ECM remodelling, and specifically the elevated expression of genes such as COL11A1, COL5A2 and MMP13 in epithelial cells of IDC. We propose that these expression changes could be involved in facilitating the transition from in situ disease to invasive cancer and may thus mark a critical point in disease development.
UQ Centre for Clinical Research, The University of Queensland, Herston, Brisbane, QLD, Australia.
Ana Cristina
AC
Vargas
Amy E
AE
McCart Reed
Nic
N
Waddell
Annette
A
Lane
Lynne E
LE
Reid
Chanel E
CE
Smart
Sibylle
S
Cocciardi
Leonard
L
da Silva
Sarah
S
Song
Georgia
G
Chenevix-Trench
Peter T
PT
Simpson
Sunil R
SR
Lakhani
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D024062:Collagen Type V / Q000096:biosynthesis / Q000235:genetics; D024161:Collagen Type XI / Q000096:biosynthesis / Q000235:genetics; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism*; D005109:Extracellular Matrix / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D017154:Stromal Cells / Q000378:metabolism*; D059016:Tumor Microenvironment; D000094742:Secreted Frizzled-Related Proteins
D024062:Collagen Type V; D024161:Collagen Type XI; D036341:Intercellular Signaling Peptides and Proteins; D053509:Matrix Metalloproteinase 13; D008565:Membrane Proteins; C574182:COL11A1 protein, human; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C507079:MMP13 protein, human