PIKing the right isoform: the emergent role of the p110beta subunit in breast cancer.
Class IA phosphoinositide-3'-kinases (PI3Ks) regulate many cellular processes. Despite a clear implication of PI3K in cancer, the involvement of each of its isoforms namely p110alpha and p110beta in the development of breast cancer remains elusive. Until recently, the spotlight was given to the alpha subunit; however, the p110beta isoform has now emerged as an interesting target as well. In order to determine the importance of both these subunits in breast cancer, we aimed to study the expression of p110alpha and p110beta in a series of invasive breast carcinomas. We constructed tissue microarrays from 315 invasive breast carcinomas and performed immunohistochemistry for p110alpha and beta, correlating the expression patterns with clinicopathological parameters. Furthermore, overall survival was analysed through Kaplan-Meier survival curves and Cox regression. We found that p110 subunits are expressed in 23.8% of invasive breast carcinomas, of which 11.8% express p110alpha and 15.2% p110beta. The p110alpha positive tumours correlated with hormone receptor (HR) expression, and were not associated with overall survival. The membrane expression of p110beta was associated with worse prognosis. This was due to its link to HER2-overexpression, lower age of onset, higher grade, lymph node involvement, distant metastasis and was inversely associated with HR status. Furthermore, p110beta expression was associated with worse overall survival. Importantly our results indicate a role for the beta subunit in the development/progression of HER2-overexpressing tumours, highlighting possible therapeutic associations between HER2 and p110beta inhibitors.
IPATIMUP: Institute of Molecular Pathology and Immunology of the University of Porto, University of Porto, Rua Dr Roberto Frias s/n, 4200-465, Porto, Portugal.
Silvia
S
Carvalho
Fernanda
F
Milanezi
José Luís
JL
Costa
Isabel
I
Amendoeira
Fernando
F
Schmitt
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011379:Prognosis; D040081:Protein Array Analysis; D021122:Protein Subunits / Q000502:physiology
D014408:Biomarkers, Tumor; D021122:Protein Subunits; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C497132:PIK3CB protein, human; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human