title: Somatic mutation and gain of copy number of PIK3CA in human breast cancer.
abstract: BACKGROUND
  Phosphatidylinositol 3-kinases (PI3Ks) are a group of lipid kinases that regulate signaling pathways involved in cell proliferation, adhesion, survival, and motility. Even though PIK3CA amplification and somatic mutation have been reported previously in various kinds of human cancers, the genetic change in PIK3CA in human breast cancer has not been clearly identified.
  
  
  METHODS
  Fifteen breast cancer cell lines and 92 primary breast tumors (33 with matched normal tissue) were used to check somatic mutation and gene copy number of PIK3CA. For the somatic mutation study, we specifically checked exons 1, 9, and 20, which have been reported to be hot spots in colon cancer. For the analysis of the gene copy number, we used quantitative real-time PCR and fluorescence in situ hybridization. We also treated several breast cancer cells with the PIK3CA inhibitor LY294002 and compared the apoptosis status in cells with and without PIK3CA mutation.
  
  
  RESULTS
  We identified a 20.6% (19 of 92) and 33.3% (5 of 15) PIK3CA somatic mutation frequency in primary breast tumors and cell lines, respectively. We also found that 8.7% (8 of 92) of the tumors harbored a gain of PIK3CA gene copy number. Only four cases in this study contained both an increase in the gene copy number and a somatic mutation. In addition, mutation of PIK3CA correlated with the status of Akt phosphorylation in some breast cancer cells and inhibition of PIK3CA-induced increased apoptosis in breast cancer cells with PIK3CA mutation.
  
  
  CONCLUSIONS
  Somatic mutation rather than a gain of gene copy number of PIK3CA is the frequent genetic alteration that contributes to human breast cancer progression. The frequent and clustered mutations within PIK3CA make it an attractive molecular marker for early detection and a promising therapeutic target in breast cancer.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA. gwu10@jhmi.edu
authors.forename: Guojun
authors.initials: G
authors.lastname: Wu
authors.forename: Mingzhao
authors.initials: M
authors.lastname: Xing
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mambo
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Junwei
authors.initials: J
authors.lastname: Liu
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Guo
authors.forename: Aditi
authors.initials: A
authors.lastname: Chatterjee
authors.forename: David
authors.initials: D
authors.lastname: Goldenberg
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Gollin
authors.forename: Saraswati
authors.initials: S
authors.lastname: Sukumar
authors.forename: Barry
authors.initials: B
authors.lastname: Trink
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D002867:Chromones / Q000494:pharmacology; D002874:Chromosome Mapping; D058534:Class I Phosphatidylinositol 3-Kinases; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D009367:Neoplasm Staging; D009369:Neoplasms / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016133:Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D002867:Chromones; D058534:Class I Phosphatidylinositol 3-Kinases; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C484760:PIK3CA protein, human