Potential use of PI3K pathway effectors and associated microRNAs as biomarkers of breast cancer prognosis

María Cecilia Perrone¹, Karen Graña¹, Andrea Werbach¹, María Jimena Rodríguez¹, Marina Riggio¹, Diego Enrico², Pablo Mando², Mora Amat², Virginia Novaro¹,

PI3K/AKT/mTOR pathway is frequently altered in breast tumors and has consequently become a promising therapeutic target; therefore, novel biomarkers are in need. In luminal breast cancer cell lines, we have previously found that AKT isoforms play distinct roles in tumor progression, with AKT1 promoting cell proliferation and AKT2 favoring cell migration and invasion. To further investigate the potential use of these proteins as breast cancer progression biomarkers, we analyzed tumor histology and expression of AKT1, AKT2 and downstream S6 phosphorylation (pS6) by immunohistochemistry in 55 luminal breast cancer samples. Our results showed that AKT1 expression decreased with greater tumor stage and Nottingham score, while AKT2 and pS6 were associated with poor prognostic factors such as higher nuclear grade and Nottingham score. We next performed RT-qPCR to evaluate the tumor expression of AKT-associated microRNAs and found that miR-34a and miR-126 correlated positively with AKT1 and negatively with AKT2 expression. In sum, low AKT1 and high AKT2 and pS6 levels appear to be associated with poor prognostic markers in luminal breast tumors. Moreover, evaluating microRNAs that are differentially associated with AKT1 and AKT2 isoforms could potentially be an advantageous tool to assess tumor prognosis in patient blood samples.