Data from Gene Expression Profiling in True Interval Breast Cancer Reveals Overactivation of the mTOR Signaling Pathway

Abstract

<div>Abstract<p><b>Background:</b> 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.</p><p><b>Methods:</b> 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 (<i>n</i> = 12; <i>n</i> = 79) by immunohistochemistry and in 24 tumors (<i>n</i> = 8; <i>n</i> = 16) by reverse transcription quantitative PCR (RT-qPCR), in true interval and screen-detected cancers, respectively.</p><p><b>Results:</b> Exploratory gene expression analysis identified 1,060 differentially expressed genes (unadjusted <i>P</i> < 0.05) between study groups. On the basis of biologic implications, four genes were further validated: <i>ceruloplasmin</i> (<i>CP</i>) and <i>ribosomal protein S6 kinase, 70 kDa, polypeptide 2</i> (<i>RPS6KB2</i>), both upregulated in true interval cancers; and <i>phosphatase and tensin homolog</i> (<i>PTEN</i>) and <i>transforming growth factor beta receptor III</i> (<i>TGFBR3</i>), downregulated in true interval cancers. Their differential expression was confirmed by RT-qPCR and immunohistochemistry, consistent with mTOR pathway overexpression in true interval cancers.</p><p><b>Conclusions:</b> 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.</p><p><b>Impact:</b> Linking epidemiologic factors and mTOR activation may be the basis for future personalized screening strategies in women at risk of true interval cancers. <i>Cancer Epidemiol Biomarkers Prev; 23(2); 288–99. ©2013 AACR</i>.</p></div>