Akt2 inhibition enables the forkhead transcription factor FoxO3a to have a repressive role in estrogen receptor alpha transcriptional activity in breast cancer cells.
Estrogen receptor alpha (ER) and the insulin-like growth factor I receptor (IGF-IR) pathways are engaged in a functional cross talk in breast cancer, promoting tumor progression and increased resistance to anticancer treatments and radiotherapy. Here, we introduce new mechanisms through which proteins of the IGF-I/IGF-IR signaling pathway may regulate ER function in the absence of ligand. Our results indicate that in ER-positive breast cancer cells, Akt2 modulates ER transcriptional activity at multiple levels, including (i) the regulation of ER expression and its nuclear retention and (ii) the activation of one of its downstream targets, the Forkhead transcription factor FoxO3a. FoxO3a colocalizes and coprecipitates with ER in the nucleus, where it binds to Forkhead-responsive sequences on the ER target pS2/TFF-1 promoter; in addition, FoxO3a silencing leads to an increase of ER transcriptional activity, suggesting a repressive role of the Forkhead transcription factor in ER function. Moreover, 17beta-estradiol upregulates FoxO3a levels, which could represent the basis for an ER-mediated homeostatic mechanism. These findings provide further evidence of the importance of mediators of the growth factor signaling in ER regulation, introducing the Akt2/FoxO3a axis as a pursuable target in therapy for ER-positive breast cancer.
Morelli
Catia
C
Department of Pharmaco-Biology, University of Calabria, 87036 Arcavacata di Rende, Italy.
Lanzino
Marilena
M
Garofalo
Cecilia
C
Maris
Pamela
P
Brunelli
Elvira
E
Casaburi
Ivan
I
Catalano
Stefania
S
Bruno
Rosalinda
R
Sisci
Diego
D
Andò
Sebastiano
S
D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic
D047628:Estrogen Receptor alpha; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt