title: AKT1 and AKT2 isoforms play distinct roles during breast cancer progression through the regulation of specific downstream proteins.
abstract: The purpose of this study was to elucidate the mechanisms associated with the specific effects of AKT1 and AKT2 isoforms in breast cancer progression. We modulated the abundance of specific AKT isoforms in IBH-6 and T47D human breast cancer cell lines and showed that AKT1 promoted cell proliferation, through S6 and cyclin D1 upregulation, but it inhibited cell migration and invasion through β1-integrin and focal adhesion kinase (FAK) downregulation. In contrast, AKT2 promoted cell migration and invasion through F-actin and vimentin induction. Thus, while overexpression of AKT1 promoted local tumor growth, downregulation of AKT1 or overexpression of AKT2 promoted peritumoral invasion and lung metastasis. Furthermore, we evaluated The Cancer Genome Atlas (TCGA) dataset for invasive breast carcinomas and found that increased AKT2 but not AKT1 mRNA levels correlated with a worse clinical outcome. We conclude that AKT isoforms play specific roles in different steps of breast cancer progression, with AKT1 involved in the local tumor growth and AKT2 involved in the distant tumor dissemination, having AKT2 a poorer prognostic value and consequently being a worthwhile target for therapy.
authors.affiliation: Instituto de Biología y Medicina Experimental (IBYME), Vuelta de Obligado 2490 Buenos Aires (1428), Argentina.
authors.forename: Marina
authors.initials: M
authors.lastname: Riggio
authors.affiliation: Instituto de Biología y Medicina Experimental (IBYME), Vuelta de Obligado 2490 Buenos Aires (1428), Argentina.
authors.forename: María C
authors.initials: MC
authors.lastname: Perrone
authors.affiliation: Instituto de Biología y Medicina Experimental (IBYME), Vuelta de Obligado 2490 Buenos Aires (1428), Argentina.
authors.forename: María L
authors.initials: ML
authors.lastname: Polo
authors.affiliation: Instituto de Biología y Medicina Experimental (IBYME), Vuelta de Obligado 2490 Buenos Aires (1428), Argentina.
authors.forename: María J
authors.initials: MJ
authors.lastname: Rodriguez
authors.affiliation: Instituto de Biología y Medicina Experimental (IBYME), Vuelta de Obligado 2490 Buenos Aires (1428), Argentina.
authors.forename: María
authors.initials: M
authors.lastname: May
authors.affiliation: Centro de Investigaciones Inmunológicas Básicas y Aplicadas. Fac. Ciencias Médicas - Universidad Nacional La Plata (1900), Argentina.
authors.forename: Martín
authors.initials: M
authors.lastname: Abba
authors.affiliation: Instituto de Biología y Medicina Experimental (IBYME), Vuelta de Obligado 2490 Buenos Aires (1428), Argentina.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lanari
authors.affiliation: Instituto de Biología y Medicina Experimental (IBYME), Vuelta de Obligado 2490 Buenos Aires (1428), Argentina.
authors.forename: Virginia
authors.initials: V
authors.lastname: Novaro
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D014183:Transplantation, Heterologous
chemical_list: D000199:Actins; D019938:Cyclin D1; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt