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Cancer Epidemiol Biomarkers Prev. 2014 Feb;23(2):288-99. doi: 10.1158/1055-9965.EPI-13-0761. Epub 2013 Dec 17.

Gene expression profiling in true interval breast cancer reveals overactivation of the mTOR signaling pathway.

Author information

1
Authors' Affiliations: Departments of Pathology and Immunology, IIS-Fundación Jiménez Díaz, Madrid; Cancer Research Program; Microarray Core Facility (SAM), IMIM (Hospital del Mar Medical Research Institute); Department of Epidemiology and Evaluation, Hospital del Mar; Research Network on Health Services in Chronic Diseases (REDISSEC); Departments of Pathology, Medical Oncology, and Radiology Department, Hospital del Mar; and Universitat Pompeu Fabra, Barcelona, Spain.

Abstract

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.

PMID:
24347552
DOI:
10.1158/1055-9965.EPI-13-0761
[Indexed for MEDLINE]
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