title: Analysis of PIK3CA Mutations and Activation Pathways in Triple Negative Breast Cancer.
abstract: BACKGROUND
  Triple Negative Breast Cancer (TNBC) accounts for 12-24% of all breast carcinomas, and shows worse prognosis compared to other breast cancer subtypes. Molecular studies demonstrated that TNBCs are a heterogeneous group of tumors with different clinical and pathologic features, prognosis, genetic-molecular alterations and treatment responsivity. The PI3K/AKT is a major pathway involved in the regulation of cell survival and proliferation, and is the most frequently altered pathway in breast cancer, apparently with different biologic impact on specific cancer subtypes. The most common genetic abnormality is represented by PIK3CA gene activating mutations, with an overall frequency of 20-40%. The aims of our study were to investigate PIK3CA gene mutations on a large series of TNBC, to perform a wider analysis on genetic alterations involving PI3K/AKT and BRAF/RAS/MAPK pathways and to correlate the results with clinical-pathologic data.
  
  
  METHODS
  PIK3CA mutation analysis was performed by using cobas® PIK3CA Mutation Test. EGFR, AKT1, BRAF, and KRAS genes were analyzed by sequencing. Immunohistochemistry was carried out to identify PTEN loss and to investigate for PI3K/AKT pathways components.
  
  
  RESULTS
  PIK3CA mutations were detected in 23.7% of TNBC, whereas no mutations were identified in EGFR, AKT1, BRAF, and KRAS genes. Moreover, we observed PTEN loss in 11.3% of tumors. Deregulation of PI3K/AKT pathways was revealed by consistent activation of pAKT and p-p44/42 MAPK in all PIK3CA mutated TNBC.
  
  
  CONCLUSIONS
  Our data shows that PIK3CA mutations and PI3K/AKT pathway activation are common events in TNBC. A deeper investigation on specific TNBC genomic abnormalities might be helpful in order to select patients who would benefit from current targeted therapy strategies.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Cossu-Rocca
authors.affiliation: Department of Pathology, "A. Businco" Oncologic Hospital, ASL Cagliari, Cagliari, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Orrù
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Muroni
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanges
authors.affiliation: Epidemiology and Medical Statistics Unit, Department of Biomedical Sciences, University of Sassari, Research, Medical Education and Professional Development Unit, AOU Sassari, Sassari, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sotgiu
authors.affiliation: Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Ena
authors.affiliation: Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Pira
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Murgia
authors.affiliation: Department of Pathology, AOU Sassari, Sassari, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Manca
authors.affiliation: Department of Pathology, AOU Sassari, Sassari, Italy.
authors.forename: Maria Gabriela
authors.initials: MG
authors.lastname: Uras
authors.affiliation: Department of Medical Oncology, ASL Nuoro, Nuoro, Italy.
authors.forename: Maria Giuseppina
authors.initials: MG
authors.lastname: Sarobba
authors.affiliation: Biomedicine Sector, Center for Advanced Studies, Research and Development in Sardinia Technology Park Polaris, Cagliari, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Urru
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: De Miglio
mesh_terms: D000328:Adult; D000368:Aged; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D066246:ErbB Receptors; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; D018631:ras Proteins