Intracellular level and localization of AKT1 and AKT2 isoforms on breast cancer outcome

MARÍA CECILIA PERRONE, MARINA RIGGIO, MARÍA JIMENA RODRIGUEZ, DIEGO ENRICO, MARÍA MAY, MARÍA LAURA POLO, DIEGO LUCAS KAEN, MARTÍN RICHARDET, EDUARDO RICHARDET, CLAUDIA LANARI AND VIRGINIA NOVARO.

Congreso; Gordon Research Conference, Hormone-Dependent Cancers; 2017

Deregulation of the PI3K/AKT/mTOR signaling pathway is strongly associated with cancer progression. It is increasingly clear that AKT1, AKT2 and AKT3 isoforms play a complex role in this disease, and the literature shows different and in some cases contradictory results on their specific roles. In this study, we found evidences that it is mainly AKT2 overexpression that has a worse prognostic value in breast cancer. First, analyzing public data from more than 800 invasive breast carcinomas from ?The Cancer Genome Atlas? (TCGA) we found that alterations in AKT2 mRNA expression, more than in AKT1, are associated with worse patient outcome. Second, and consistent with the above, we performed an immunohistochemical analysis of the abundance and localization of AKT1 and AKT2 in a cohort of 46 advanced ductal invasive breast carcinomas. We found that high nuclear AKT1 expression positively correlated with the proliferation marker Ki67, whereas high cytosolic AKT2 was associated with earlier disease progression and poorer clinical outcome. Third, in pre-clinical models derived from T47D xenografts modified to include different stages of breast cancer progression, we found that cytosolic AKT2 is prevalent in endocrine-resistant variants and specifically in areas of tumor invasion. These evidences, together with our published data in T47D cells showing that AKT2 upregulates proteins involved in cell invasion such as F-actin and vimentin; whereas AKT1 upregulates proteins that promote proliferation and survival such as Cyclin D1 and pS6, suggest that the intracellular levels and compartmentalization correlate with the functional differences of each isoform. 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.