Involvement of the FOXO6 transcriptional factor in breast carcinogenesis.

François Lallemand,Bernard S Lopez,Ambre Petitalot,Ivan Bieche,Nicole Dalla-Venezia,Sophie Zinn-Justin,Anne Schnitzler,Walid Chemlali,Sophie Vacher,Rosette Lidereau,Sandrine M Caputo,Karim Taouis,Leanne De Koning

doi:10.18632/oncotarget.23779

Abstract

In mammals, FOXO transcriptional factors form a family of four members (FOXO1, 3, 4, and 6) involved in the modulation proliferation, apoptosis, and carcinogenesis. The role of the FOXO family in breast cancer remains poorly elucidated. According to the cellular context and the stage of the disease, FOXOs can have opposite effects on carcinogenesis. To study the role of FOXOs in breast carcinogenesis in more detail, we examined their expression in normal tissues, breast cell lines, and a large series of breast tumours of human origin. We found a very low physiological level of FOXO6 expression in normal adult tissues and high levels of expression in foetal brain. FOXO gene expressions fluctuate specifically in breast cancer cells compared to normal cells, suggesting that these genes may have different roles in breast carcinogenesis. For the first time, we have shown that, among the various FOXO genes, only FOXO6 was frequently highly overexpressed in breast cell lines and tumours. We also found that inhibition of the endogenous expression of FOXO6 by a specific siRNA inhibited the growth of the human breast cell lines MDA-MB-468 and HCC-38. FACS and Western blot analysis showed that inhibition of endogenous expression of FOXO6 induced accumulation of cells in G0/G1 phase of the cell cycle, but not apoptosis. These results tend to demonstrate that the overexpression of the human FOXO6 gene that we highlighted in the breast tumors stimulates breast carcinogenesis by activating breast cancer cell proliferation.

Highlights

The FOXO genes encode the proteins of the O-subfamily belonging to the large family of forkhead transcription factors that share a highly conserved DNAbinding domain, the forkhead domain or winged-helix domain [1, 2]
The results reported by Sisci et al suggest that the role of FOXO3 in breast cancer is linked to the oestrogen receptor α (ERα) status: in ERα-positive cells, FOXO3 inhibits breast carcinogenesis, while in ERα-negative cells, FOXO3 tend to promote breast carcinogenesis [15]
The highest FOXO1 expression was detected in the uterus, skeletal muscle and ovary, the highest expression FOXO3 was detected in bone narrow and skeletal muscle, and the highest FOXO4 expression was detected in the placenta, adrenal gland, ovary and skeletal muscle

Summary

Introduction

The FOXO genes encode the proteins of the O-subfamily belonging to the large family of forkhead transcription factors that share a highly conserved DNAbinding domain, the forkhead domain or winged-helix domain [1, 2]. The transcriptional activity of FOXO proteins is regulated by posttranslational modifications, such as acetylation, ubiquitination, and phosphorylation [1]. FOXOs are negatively modulated by growth factors, such as insulin, via activation of the PI3K-AKT pathway. Activation of this pathway induces phosphorylation of FOXO proteins by AKT, leading to their exclusion from the nucleus, thereby terminating their ability to induce target genes [6, 7]. Human tumours frequently harbour activating mutations in PIK3CA (or p110α, the catalytic subunit of PI3K) or inactivating mutations in PTEN (negative regulator of the PI3K-AKT pathway), leading to over-stimulation of PI3KAKT pathway activity [8]

Methods

Results

Conclusion