Molecular biomarkers associated with mutant BRCAl breast cancer patients

Abstract

The presence of mutations in the BRCA1 gene has been linked to a worse overall prognosis in the case of breast cancer. Furthermore, its mutational status has been linked to susceptibility or resistance to certain adjuvant therapies used in the treatment of the cancer. This study aims at investigating the feasibility of using phospho-Akt (Serine-473) status as a biomarker for mutant BRCA1 gene and generation of a cellular model for the measurement of Akt activation with respect to BRCA1 mutational status. The use of p-Akt as a biomarker is supported by other studies which showed that inhibition of BRCA1 activity leads to increased phosphorylation of Akt (Xiang, et aI., 2008). Formalin-fixed paraffin-embedded (FFPE) triple negative breast cancer samples were stained with an antibody raised against phosphorylated Ser-473 in Akt (p-Akt (S473)) and an attempt was made to correlate the intensity of staining with the presence of mutations in the BRCA1 gene. A subset of triple negative breast cancer cases (53%) was found to have high p-Akt. Cases with high Akt activation may derive greater benefit from therapies targeting the Akt/mTor pathway. This is supported by the finding that FTY720 (at l/µM), an activator of PP2A (a phosphatase that inhibits Akt activity) suppresses Akt activation in MCF-7 and HCC1937 cells stimulated by IGF-1 (a stimulator of Akt), indicating that p-Akt (S473) is a potential predictive biomarker. Mutational analysis of triple negative breast cancers has revealed the presence of two novel . mutations: IVS2+38insTA in the second intron of BR CA 1, and 5384G>T in exon 20. Further studies are required to investigate the function of the identified mutations in BRCA1 and their significance in disease.