Mutations of BRCA genes are an independent poor prognostic factor in the development of prostate cancer. It is known that the mutations BRCA1 / 2 are most often associated with the AKT / m-TOR signaling cascade hyperactivation. The purpose was to study the AKT/m-TOR pathway components in castration-resistant prostate cancer patient, depending on the presence of the BRCA mutations.
40 patients with prostate cancer, 15 patients with castration-resistant prostate cancer and 20 patients with benign hyperplasia are enrolled in the investigation. The expression of AKT, c-Raf, GSK-3, PDK1, and m-TOR, 70-S64, E-BP1 was determined by real-time PCR. The BRCA 1/2 mutation was determined in allele-specific PCR in real time.
Activation of the AKT / m-TOR signaling cascade was detected in prostate cancers. The high levels of AKT and m-TOR expression were revealed. The increase in the level of phosphatase PTEN was found in benign hyperplasia and cancer tissues. The level of mRNA 4E-BP1 was decreased in castration-resistant prostate cancer patients. At the next stage of the study, the incidence of inherited BRCA1 / 2 mutations were studied in patients with castration-resistant cancer. The BRCA1-5382insC mutation was detected in 3 patients (20%), BRCA1-4153delA – in 5 patients (33%), BRCA1-185delAG – in 2 patients (13%), BRCA1-T300G – in 2 patients (13%) and BRCA2-6174del – in 4 patients (27%). BRCA1-deficiency activates the AKT oncogenic pathway, one of the most common alterations associated with human malignancy. Mutation of BRCA1 gene increases the phosphorylation and the kinase activity of AKT. The decreased AKT expression in cancers was found in patients with BRCA1-5382insC mutation. Mutation of BRCA1-4153delA increased expression of 70S, m-TOR, in the presence of BRCA1-T300G - increased PTEN. The inherited BRCA2-6174del mutation was correlated with the increased expression of AKT.
Therefore, the development of PCa is accompanied by activation of this signaling cascade, even more pronounced in the presence of mutations BRCA2-6174del, BRCA1-4153delA, BRCA1-T300G. It should be noted that the frequency of occurrence of these mutations varies from 13 to 33%. At the same time, a greater accumulation of hereditary mutations BRCA1-4153delA and BRCA2-6174del was noted.
Clinical trial identification
Legal entity responsible for the study
Tomsk National Research Medical Center.
Has not received any funding.
The author has declared no conflicts of interest.