Differential role of AKT1 and AKT2 isoforms in the malignant phenotype of two human breast cancer cell lines.

MARINA RIGGIO, MARÍA LAURA POLO, CLAUDIA LANARI AND VIRGINIA NOVARO

Bariloche

Simposio; SISTAM The Second South American Spring Symposium in Signal Transduction and Molecular Medicine; 2012

The PI3K/Akt pathway has been implicated in human breast cancer, especially involved in acquired resistance to endocrine therapy. Recent works propose that whereas Akt1 isoform induces growth and inhibits migration of breast cancer cells, Akt2 isoform promotes metastatic dissemination of tumor cells. Previously, in a mouse model of breast cancer and in the IBH-7 human cell line, we demonstrated that overactivation of Akt1 by using a myristoilated variant, was sufficient to induce ligand-independent activation of steroid receptors, and to bypass the requirement of hormone supply to induce mammary tumors in nude mice. Moreover, Akt1 increased E-cadherin and FAK in breast cancer cells and the resultant tumors are ductal-type. In this work, we used different constructs to overactivate or silence specifically Akt1 and Akt2 isoforms to analyze the resultant phenotype in two breast cancer cell lines. When cultured on plastic, both shAkt1 and shAkt2 reduces pFAK and E-cadherin in breast cancer cells. Nevertheless, we have not seen a differential effect by the two Akt isoforms on cell motility evaluated by the wound healing assay. On the contrary, when cultured in a 3D system on Matrigel, IBH-6 and IBH-7-myrAKT1 cells formed larger colonies than control cells, with an increase in E-cadherin and F-actin indicating increased cell-cell adhesion. This effect was reverted by silencing Akt1. These results suggest that differential roles of Akt1 and Akt2 are cell context-dependent. Future analysis in vivo will provide insight about the roles of Akt1 and Akt2 in hormone-dependence, tissue architecture, endocrine response and aggressiveness of the tumor.