Dissecting the role of AKT isoforms in breast tumor growth and aggressiveness

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

Stowe, VT

Congreso; Gordon Research Mammary Gland Biology; 2013

There is a general consensusthat the phosphoinositide-3 kinase (PI3K)/AKT pathway is frequently mutated in the majority of solid tumors. However, there is increasing evidence that Akt1 and Akt2 isoforms have opposing roles in tumor progression. Akt1 is mainly involved in tumor initiation and in the maintenance of an organized actin cytoskeleton. On the contrary, Akt2 ismainly involved in tumor dissemination, migration and it has been related to the epithelial-mesenchymal transition (EMT). Consistent with those findings, by overactivation or silencing of specific Akt1 and Akt2 isoforms in the estrogen-independent ER/PR+ human IBH-6 cell line derived from a primary invasive ductal breast carcinoma, we have found that Akt1 has a major role promoting tumor growth, cell proliferation and cell-cell adhesionthrough an increase in FAK and E-cadherin. Furthermore, overactivation of Akt1 sensitizes breast tumors to the treatment with antiestrogens, Tamoxifenor ICI182780, as well as to the mTOR inhibitor rapamycin. On the other hand, Akt2 is prevalent in inducing vimentin expressionand modulating cell invasion through Matrigel, two indicators of an EMT phenomenon. We also have shown that the differential roles of Akt1 and Akt2 are cell context- and cell type-dependent. Current analyses in vivousing IBH-6 xenograft and an experimental mouse model of breast cancerare focused on providing insights about the specific pathwaysand signaling driven by Akt1 and Akt2 that regulate growth rate, hormone-dependence, endocrine response,tissue architecture, invasiveness and aggressiveness of mammarytumors. This preclinical testing may help to find downstream molecules of the PI3K/AKT pathway as prognostic markers and/or therapeutic targets in breast cancer that should be brought forward into the clinic.