IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Role of PI3K/AKT signaling pathway in breast cancer behavior
Autor/es:
RIGGIO, MARINA; POLO, MARIA LAURA; MAY, M; LANARI, C; NOVARO, VIRGINIA
Lugar:
Vermont
Reunión:
Conferencia; Gordon Research Conference- Mammary gland biology; 2013
Resumen:
There is a general consensus that 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 is mainly 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 adhesion through an increase in FAK and E-cadherin. Furthermore, overactivation of Akt1 sensitizes breast tumors to the treatment with antiestrogens, Tamoxifen or ICI182780, as well as to the mTOR inhibitor rapamycin. On the other hand, Akt2 is prevalent in inducing vimentin expression and 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 vivo using IBH-6 xenograft and an experimental mouse model of breast cancer are focused on providing insights about the specific pathways and signaling driven by Akt1 and Akt2 that regulate growth rate, hormone-dependence, endocrine response, tissue architecture, invasiveness and aggressiveness of mammary tumors. 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.