title: PI3K pathway activation in high-grade ductal carcinoma in situ--implications for progression to invasive breast carcinoma.
abstract: OBJECTIVE
  To assess the prevalence of phosphoinositide 3-kinase (PI3K) pathway alterations in pure high-grade ductal carcinoma in situ (DCIS) and DCIS associated with invasive breast cancer (IBC), and to determine whether DCIS and adjacent IBCs harbor distinct PI3K pathway aberrations.
  
  
  METHODS
  Eighty-nine cases of pure high-grade DCIS and 119 cases of high-grade DCIS associated with IBC were characterized according to estrogen receptor (ER) and HER2 status, subjected to immunohistochemical analysis of PTEN, INPP4B, phosphorylated (p)AKT and pS6 expression, and to microdissection followed by Sequenom genotyping of PIK3CA and AKT1 hotspot mutations.
  
  
  RESULTS
  Alterations affecting the PI3K pathway were found in a subset of pure DCIS and DCIS adjacent to IBC. A subtype-matched comparison of pure DCIS and DCIS adjacent to IBC revealed that PIK3CA hotspot mutations and pAKT expression were significantly more prevalent in ER-positive/HER2-negative DCIS adjacent to IBC (P values, 0.005 and 0.043, respectively), and that in ER-negative/HER2-positive cases INPP4B loss of expression was more frequently observed in pure DCIS (a P value of 0.013). No differences in the parameters analyzed were observed in a pairwise comparison of the in situ and invasive components of cases of DCIS and adjacent IBC. Analysis of the PIK3CA-mutant allelic frequencies in DCIS and synchronous IBC revealed cases in which PIK3CA mutations were either restricted to the DCIS or to the invasive components.
  
  
  CONCLUSIONS
  Molecular aberrations affecting the PI3K pathway may play a role in the progression from high-grade DCIS to IBC in a subset of cases (e.g., a subgroup of ER-positive/HER2-negative lesions).
authors.affiliation: Authors' Affiliations: Breast Service, Department of Surgery; Departments of Pathology; and Medicine; and the Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Rita A
authors.initials: RA
authors.lastname: Sakr
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
authors.forename: Sarat
authors.initials: S
authors.lastname: Chandarlapaty
authors.forename: Victor P
authors.initials: VP
authors.lastname: Andrade
authors.forename: Elena
authors.initials: E
authors.lastname: Guerini-Rocco
authors.forename: Dilip
authors.initials: D
authors.lastname: Giri
authors.forename: Charlotte K Y
authors.initials: CK
authors.lastname: Ng
authors.forename: Catherine F
authors.initials: CF
authors.lastname: Cowell
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.forename: Tari A
authors.initials: TA
authors.lastname: King
mesh_terms: D000483:Alleles; D014408:Biomarkers, Tumor; D001706:Biopsy; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007150:Immunohistochemistry; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases