DCIS Heterogeneity: An Integrated RNA-miRNA Analysis
Juan C Moreno, Ranju Nair, Naomi A Miller, Bruce J Youngson, Vladimir Iakovlev, David McCready, Susan J Done. Campbell Family Institute for Breast Cancer Research, Toronto, ON, Canada; University Health Network, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada; St. Michael's Hospital, Toronto, ON, Canada
Background: Ductal carcinoma in situ (DCIS) is a heterogeneous, pre-invasive malignancy that can be a precursor to invasive breast cancer, however not all lesions progress. Limited ability to prognosticate progression leads to over treatment of a significant number of patients. Mapping RNA and miRNA molecular changes simultaneously may provide a better understanding of DCIS heterogeneity and help us predict its clinical behavior.
Design: Five cases of extensive DCIS were selected. From each case six areas (5 DCIS, 1 normal) were microdissected. The epithelium and the peri-lesional stroma were microdissected separately. RNA and miRNA were extracted and microarray analysis performed.
Results: An epithelial RNA signature of 317 probes clusters samples into two groups, one overexpressing genes involved in cell proliferation, and the other overexpressing genes involved in nuclear translocation of proteins, protein folding and NF-κB signalling. Three cases (60%) had samples belonging to both groups. A stromal RNA signature clusters samples into two groups, one enriched for positive regulators of transcription, gene expression and STAT3 phosphorylation, the other overexpressing genes involved in cell junction organization and assembly. Four cases (80%) had samples belonging to both groups. A signature of 63 miRNAs separate epithelial samples into three distinct groups, and a signature of 42 miRNAs cluster stromal samples into 4 groups. In epithelial samples, 50% (15/30) of the overexpressed miRNAs control 30 (9%) of the over/underexpressed genes in the RNA signature. In stromal samples 26 out of 45 miRNAs control 125 (13%) genes in the stromal signature.
Conclusions: We analyzed RNA and miRNA simultaneously on the same samples. Results show that DCIS and adjacent stroma with different signatures coexist within the same breast. Signatures include several genes known to be altered in breast cancer. Interestingly even apparently normal stromal samples have signatures that cluster them into groups with proliferating or protective genes. RNA signatures that support proliferation in both the epithelium and the stroma are seen in 43% (7/16) of samples. These studies add to our understanding of the biology of DCIS and may result in genetic signatures which if present can predict for progression to invasive breast cancer.
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 32, Tuesday Morning