Opposite roles of Akt1 and Akt2 in cell migration and invasion through b1-integrin regulation

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

Bariloche

Congreso; SISTAM The Third South American Spring Symposium in Signal Transduction and Molecular Medicine; 2015

Despite the improvement in the early diagnosis and the use of modern therapies, breast cancer is the second cause of death, after lung cancer, in women around the world, and this is mainly due to metastasis development in distant organs. PI3K/Akt pathway is deregulated in almost 50% of breast carcinomas, and is associated to therapy resistance. At the present time there are increasing clinical trials that combine endocrine treatments with PI3K/Akt inhibitors to delay tumor resistance and to avoid tumor progression. However, these inhibitors do not distinguish between the isoform specific function of Akt1, Akt2 and Akt3. The aim of this work was to study Akt1 and Akt2 isoforms, focusing on their particular role in cell migration and invasion in IBH-6 and T47D human breast cancer cell lines. We stably transfected the cells to specifically overactivate (myrAkt) or inhibit (shAkt) Akt1 or Akt2 and analyzed the resulting phenotype in cell culture and in cells growing as xenografts. We found that, while myrAkt1 had no effect on cell adhesion, shAkt1 increased cellular ability to migrate and to invade extracellular matrix substrate Matrigel. Contrarily, myrAkt2 cells showed a more invasive phenotype as compared to control cells, while shAkt2 cells decreased cell migration and invasion. These phenotypes were accompanied by an opposite regulation in β1-Integrin, pFAK and Vimentin expression levels. Interestingly, in IBH-6 and T47D xenograft studies we observed that while myrAkt1 tumors grew faster, shAkt1 cells grew even more slowly than control tumors, but displayed a ducto-lobulillar invasive phenotype. Contrarily, shAkt2 and myrAkt2 tumors showed no differences in growth rate as compared to control tumors. However, whereas an undifferentiated and infiltrating phenotype was observed in the myrAkt2 tumors, no infiltrating morphology was observed in shAkt2 counterparts. Altogether, these results indicate that Akt1 and Akt2 isoforms have different and, in some cases, opposite functions during breast cancer progression. The analysis of the status of each isoform-driven pathway is relevant in the design of targeted therapies that could be more effective and selective at each tumor stage. PREMIO AL MEJOR POSTER.