title: Gene expression profiling in true interval breast cancer reveals overactivation of the mTOR signaling pathway.
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.
  
  
  CONCLUSIONS
  Linking epidemiologic factors and mTOR activation may be the basis for future personalized screening strategies in women at risk of true interval cancers.
authors.affiliation: 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.
authors.forename: Federico
authors.initials: F
authors.lastname: Rojo
authors.forename: Laia
authors.initials: L
authors.lastname: Domingo
authors.forename: Maria
authors.initials: M
authors.lastname: Sala
authors.forename: Sandra
authors.initials: S
authors.lastname: Zazo
authors.forename: Cristina
authors.initials: C
authors.lastname: Chamizo
authors.forename: Silvia
authors.initials: S
authors.lastname: Menendez
authors.forename: Oriol
authors.initials: O
authors.lastname: Arpi
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: Corominas
authors.forename: Rafael
authors.initials: R
authors.lastname: Bragado
authors.forename: Sonia
authors.initials: S
authors.lastname: Servitja
authors.forename: Ignasi
authors.initials: I
authors.lastname: Tusquets
authors.forename: Lara
authors.initials: L
authors.lastname: Nonell
authors.forename: Francesc
authors.initials: F
authors.lastname: Macià
authors.forename: Juan
authors.initials: J
authors.lastname: Martínez
authors.forename: Ana
authors.initials: A
authors.lastname: Rovira
authors.forename: Joan
authors.initials: J
authors.lastname: Albanell
authors.forename: Xavier
authors.initials: X
authors.lastname: Castells
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D055088:Early Detection of Cancer; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D046228:Microarray Analysis; D008875:Middle Aged; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*
chemical_list: C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases