Journal
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
Volume 23, Issue 2, Pages 288-299Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1055-9965.EPI-13-0761
Keywords
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Funding
- Instituto de Salud Carlos III- FEDER [PI12/00680, PI12/01552, PI09/01153, PI11/01296]
- Pla Director d'Oncologia de Catalunya
- [RD12/0036/0051]
- [RD09/0076/0036]
- [RD09/0076/0101]
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Background: The development and progression of true interval breast cancers (tumors that truly appear after a negative screening mammogram) is known to be different from screen-detected cancers. However, the worse clinical behavior of true interval cancers is not fully understood from a biologic basis. We described the differential patterns of gene expression through microarray analysis in true interval and screen-detected cancers. Methods: An unsupervised exploratory gene expression profile analysis was performed on 10 samples (true interval cancers 5; screen-detected cancers 5) using Affymetrix Human Gene 1.0ST arrays and interpreted by Ingenuity Pathway Analysis. Differential expression of selected genes was confirmed in a validation series of 91 tumors (n = 12; n = 79) by immunohistochemistry and in 24 tumors (n = 8; n = 16) by reverse transcription quantitative PCR (RT-qPCR), in true interval and screen-detected cancers, respectively. Results: Exploratory gene expression analysis identified 1,060 differentially expressed genes (unadjusted P < 0.05) between study groups. On the basis of biologic implications, four genes were further validated: ceruloplasmin (CP) and ribosomal protein S6 kinase, 70 kDa, polypeptide 2 (RPS6KB2), both upregulated in true interval cancers; and phosphatase and tensin homolog (PTEN) and transforming growth factor beta receptor III (TGFBR3), downregulated in true interval cancers. Their differential expression was confirmed by RT-qPCR and immunohistochemistry, consistent with mTOR pathway overexpression in true interval cancers. Conclusions: True interval and screen-detected cancers show differential expression profile both at gene and protein levels. The mTOR signaling is significantly upregulated in true interval cancers, suggesting this pathway may mediate their aggressiveness. Impact: Linking epidemiologic factors and mTOR activation may be the basis for future personalized screening strategies in women at risk of true interval cancers.
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