A computational approach for investigating the mutational landscape of RAC-alpha serine/threonine-protein kinase (AKT1) and screening inhibitors against the oncogenic E17K mutation causing breast cancer.
Mutations in phosphatidylinositol-3-kinase (PI3KCA) have been described in 8-40% of invasive breast carcinomas, and AKT1 mutations have been characterized in 1-8% of breast carcinomas.
The hotspot mutation H1047R in the oncogenic PIK3CA gene is frequently detected in breast cancer and enhances the enzymatic activity of PI3K to activate AKT/mTOR signaling cascade.
Recent study revealed that SGK3 plays a pivotal role in Akt/protein kinase B independent signaling downstream of oncogenic PI3KCA mutations in breast cancer.
Alterations in the PI3K/AKT pathway are frequently found in cancer and are especially common in breast cancer, where it is estimated that 70% of tumors have some type of genetic alteration that could lead to pathway hyperactivation.
In this study, we examined mutations of the PI3K/AKT pathway in 75 breast carcinomas using high-resolution melting analysis and pyrosequencing, in parallel with analysis of relative expression of PIK3CA and AKT2 genes.
The somatic activation of PI3K/AKT pathway mutations, PIK3CA and AKT1, and ESR1 mutations in plasma cell-free DNA (cfDNA) has been studied as a non-invasive procedure to quickly assess and monitor disease progression or therapeutic effect in breast cancer (BC) patients, but the clinical significance of these mutations in late treatment lines (TLs) remains unclear.
Epidemiologic studies suggested that mutations of the PI3K/PTEN/AKT pathway genes are associated with cancer risk, yet no data are available for PTEN rs701848, PIK3CA rs2699887, and AKT1rs2494752 polymorphism and breast cancer(BC) risk.
Areas specifically addressed include hormonal pathways, tumor protein p53 (TP53) and AT rich interactive domain 1A (SWI-like; ARID1A) mutation, and the breast cancer 1/2, early onset (BRCA1/2) mutation/poly (ADP-ribose) polymerase 1 (PARP1), phosphatidylinositol-4,5-bisphosphate 3- kinase, catalytic subunit alpha (PI3KCA)/v-akt murine thymoma viral oncogene homolog 1 (AKT1)/mechanistic target of rapamycin (MTOR), and mitogen-activated protein kinase kinase 1 and 2 (MAP2K1/2) pathways.
Phosphatidylinositol-3-kinase (PI3K)/AKT pathway mutations are associated with cancer and phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene mutations have been observed in 25-45% of breast cancer samples.
We have performed functional analysis of six non-hotspot AKT1 pleckstrin homology domain mutants identified in recent large-scale breast cancer sequencing studies.
Similarly, carriers of 20 SNPs in PIK3R1, AKT1/2, and MAPK1 genes (signaling pathways-genetic variants) had different associations with breast cancer between strata, and the proportion of the SNP-cancer relationship explained by traits varied 45-50% between the strata.
Although PI3K/AKT mutations are associated with increased proliferation of breast cancer cells, mutations in breast cancer stem/progenitor cells subpopulations did not correlate with changes in metabolic gene expression.
Despite the small sample size, we found that the intronic variant, AKT1rs3803304, may act as a predictive biomarker in the risk of developing breast cancer in the high altitude Ecuadorian mestizo population.
These data indicate that mutations of PIK3CA play an oncogenic role in substantial fractions of ovarian and breast carcinomas, and in consideration of mutation of other components of the PI3K-AKT pathway in both tumor types, confirm the major oncogenic role of this pathway in ovarian and breast carcinomas.