AKT1 regulates AKT2 expression and sucellular localization in a human breast cáncer model

MARINA RIGGIO, MARÍA CECILIA PERRONE, MARÍA JIMENA RODRIGUEZ, CLAUDIA LANARI AND VIRGINIA NOVARO.

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias, Buenos Aires, Argentina.; 2017

The aim of this work was to study the regulation between AKT1 and AKT2 isoforms and its possible implications in breast cancer progression. Previously, in a cohort of 46 advanced ductal invasive breast carcinomas we found that high nuclear AKT1 was associated with high Ki67 index, whereas either high nuclear AKT1 or high cytosolic AKT2 were associated with earlier disease progression. Furthermore, using T47D and IBH-6 human breast cancer cell lines we selectively downregulated AKT1 (shAKT1) or AKT2 (shAKT2) isoforms. In xenograft assays we found that AKT2 inhibition (shAKT2) induced non-invasive tumors, whereas AKT1 inhibition (shAKT1) reduced tumor growth, but induced an invasive phenotype and lung metastasis. Surprisingly, we found increased AKT2 protein levels in shAKT1 cells. For this reason, we analyzed how the AKT isoform regulation could be involved in breast cancer progression. We found that T47D shAKT1 tumors, that grow with lower rate but are more invasive, express higher levels of both nuclear and cytosolic AKT2, than control (shco) tumors; while shAKT2 tumors express lower levels of nuclear and higher levels of cytosolic AKT1 than shco tumors. These results suggest a switch in AKT isoforms expression and localization that may be regulated by the isoforms themselves, along tumor progression. Moreover, data from from 825 invasive breast carcinomas from ?The Cancer Genome Atlas? (TCGA) demonstrated that alterations in AKT2 mRNA expression, more than in AKT1, are associated with worse patient outcome.In conclusion, AKT1 and AKT2 level and their subcellular localization might be used as biomarkers of breast cancer progression early in the diagnostic process to discriminate which subset of patients could progress sooner and consequently have potentially worse clinical outcomes.