Involvement of the FOXO6 transcriptional factor in breast carcinogenesis

// Francois Lallemand 1, * , Ambre Petitalot 1, 2, * , Sophie Vacher 1 , Leanne de Koning 3 , Karim Taouis 1 , Bernard S. Lopez 4 , Sophie Zinn-Justin 5 , Nicole Dalla-Venezia 6 , Walid Chemlali 1 , Anne Schnitzler 1 , Rosette Lidereau 1 , Ivan Bieche 1, 7, * and Sandrine M. Caputo 2, * 1 Service de genetique, unite de pharmacogenomique, Institut Curie, Paris, France 2 Service de genetique, unite de genetique constitutionnelle, Institut Curie, Paris, France 3 Departement de transfert, Institut Curie, Paris, France 4 CNRS UMR 8200, Gustave Roussy Cancer Institute, Universite Paris-Saclay, equipe labelisee par la Ligue contre le cancer, Villejuif, France 5 Laboratoire de biologie structurale et radiobiologie, IBITEC-S (CEA) and I2BC (UMR 9198, CEA, CNRS, Univ. Paris South), Gif-sur-Yvette, France 6 Centre de Recherche en Cancerologie de Lyon (CRCL)/INSERM U1052-CNRS UMR5286, Lyon, France 7 EA7331, Universite Paris Descartes, Paris, France * These authors contributed equally to this work Correspondence to: Sandrine M. Caputo, email: sandrine.caputo@curie.fr Keywords: gynecological cancers; cervical squamous cell carcinoma; endometrial adenocarcinoma; uc.189; prognosis Received: May 12, 2017 Accepted: December 22, 2017 Published: December 30, 2017 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.