FoxO3a transcription factor differentially modulates the metastatic potential of ER+ and ER− breast tumors

Abstract

FoxO3a (F3a) transcription factor has been reported to suppress estrogen(E2)‐dependent breast cancer cell growth and tumorigenesis through its functional interaction with the estrogen receptor α (ER). However, the role of this interplay in tumor metastasis is poorly defined and is the aim of the present study. To this purpose, F3a and its active form AAA, were over‐expressed both in ER+ and in ER− breast cancer cell lines. Our results show decreased migration and invasion of F3a/ER+ cells compared to control, paralleled by a strong upregulation of Caveolin‐1 (Cav‐1), the main constituent of caveolae that seems to function as a negative regulator of cell transformation and invasion in breast cancer, and a significant reduction of MMP‐13 mRNA. F3a mediated effects were more evident in AAA expressing cells and were emphasized by E2. On the other hand, in ER− cells, F3a and AAA increased cell migration and invasion with a concomitant induction of MMP‐13 transcripts, while no difference was observed in Cav‐1 levels. Since both Cav‐1 and MMP‐13 promoters bear Forkhead canonical motifs next to ER binding sequences, our hypothesis is that F3a exerts a protective role in ER+ breast cancers through F3a/ER mediated regulation of Cav‐1 and MMP‐13, while it could represent a bad prognostic factor in ER− breast tumors. Financial support has been provided by AIRC (Associazione Italiana Ricerca Cancro).