FoxO3a Reduces Tamoxifen Resistant Breast Cancer Aggressiveness by Inducing Integrin a5 Expression

Abstract

Resistance to endocrine therapy is still a major clinical challenge in the management of estrogen receptor positive (ER+) breast cancer (BC) patients, whose poor outcome demands additional studies. Forkhead box class O (FoxO)3a transcription factor, a bona fide oncosuppressor, has been involved in BC metastasis as well as in antiestrogen resistance. Here we demonstrate that the α5 subunit of the integrin α5β1, a well-known membrane heterodimer controlling cell surface adhesion and signaling, is a novel FoxO3a transcriptional target. FoxO3a re-expression reduces motility (wound healing and transmigration assays) of different Tamoxifen resistant BC cell lines, through the induction of α5 mRNA (qRT-PCR) and protein (Western blot) levels. FoxO3a transcriptionally regulates α5 expression by binding to specific Forkhead responsive elements located on the α5 promoter (Luciferase and ChIP assays). Accordingly, using a large-scale BC gene expression datasets from The Cancer Genome Atlas (TCGA) database, a strong positive correlation between FoxO3a and α5 in ER+ BC patients emerged. Altogether, our data unveil an additional mechanism through which FoxO3a activation/induction, by increasing α5 expression, restores a less aggressive phenotype in BC refractory to endocrine therapy.