Involvement of the FOXO6 transcriptional factor in breast carcinogenesis

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.

[1]  Shu-sen Zheng,et al.  Expression of FOXO6 is Associated With Oxidative Stress Level and Predicts the Prognosis in Hepatocellular Cancer , 2016, Medicine.

[2]  J. Demoulin,et al.  FOXO transcription factors in cancer development and therapy , 2016, Cellular and Molecular Life Sciences.

[3]  M. Bullock,et al.  FOXO factors and breast cancer: outfoxing endocrine resistance. , 2016, Endocrine-related cancer.

[4]  Zhen-hua Wang,et al.  FoxO6 inhibits cell proliferation in lung carcinoma through up-regulation of USP7. , 2015, Molecular medicine reports.

[5]  S. Vacher,et al.  ATM has a major role in the double-strand break repair pathway dysregulation in sporadic breast carcinomas and is an independent prognostic marker at both mRNA and protein levels , 2015, British Journal of Cancer.

[6]  S. Andò,et al.  The estrogen receptor α is the key regulator of the bifunctional role of FoxO3a transcription factor in breast cancer motility and invasiveness , 2013, Cell cycle.

[7]  Cui Long,et al.  FOXO6 promotes gastric cancer cell tumorigenicity via upregulation of C‐myc , 2013, FEBS letters.

[8]  Shen-Liang Chen,et al.  FoxO6 and PGC-1α form a regulatory loop in myogenic cells , 2013, Bioscience reports.

[9]  S. Ringquist,et al.  FoxO6 Integrates Insulin Signaling With Gluconeogenesis in the Liver , 2011, Diabetes.

[10]  R. Ganju,et al.  Cdc25A Regulates Matrix Metalloprotease 1 through Foxo1 and Mediates Metastasis of Breast Cancer Cells , 2011, Molecular and Cellular Biology.

[11]  F. Lallemand,et al.  Expression analysis of mitotic spindle checkpoint genes in breast carcinoma: role of NDC80/HEC1 in early breast tumorigenicity, and a two-gene signature for aneuploidy , 2011, Molecular Cancer.

[12]  B. White,et al.  Coordinate Regulation of FOXO1 by miR-27a, miR-96, and miR-182 in Breast Cancer Cells , 2009, The Journal of Biological Chemistry.

[13]  A. Toker,et al.  FOXO3a Promotes Tumor Cell Invasion through the Induction of Matrix Metalloproteinases , 2009, Molecular and Cellular Biology.

[14]  Ahmed Essaghir,et al.  The Transcription of FOXO Genes Is Stimulated by FOXO3 and Repressed by Growth Factors* , 2009, Journal of Biological Chemistry.

[15]  Chiun Hsu,et al.  Forkhead box transcription factor FOXO3a suppresses estrogen-dependent breast cancer cell proliferation and tumorigenesis , 2008, Breast Cancer Research.

[16]  G. Mills,et al.  ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation , 2008, Nature Cell Biology.

[17]  L. Cantley,et al.  Ras, PI(3)K and mTOR signalling controls tumour cell growth , 2006, Nature.

[18]  F. Lallemand,et al.  AIP4 Restricts Transforming Growth Factor-β Signaling through a Ubiquitination-independent Mechanism* , 2005, Journal of Biological Chemistry.

[19]  B. Hemmings,et al.  Advances in protein kinase B signalling: AKTion on multiple fronts. , 2004, Trends in biochemical sciences.

[20]  P. Wijchers,et al.  FoxO6, a Novel Member of the FoxO Class of Transcription Factors with Distinct Shuttling Dynamics* , 2003, Journal of Biological Chemistry.

[21]  I. Bièche,et al.  Quantitative RT-PCR reveals a ubiquitous but preferentially neural expression of the KIS gene in rat and human. , 2003, Brain research. Molecular brain research.

[22]  A. Frankfurter,et al.  Expression of stathmin family genes in human tissues: non-neural-restricted expression for SCLIP. , 2003, Genomics.

[23]  I. Bièche,et al.  Identification of CGA as a novel estrogen receptor-responsive gene in breast cancer: an outstanding candidate marker to predict the response to endocrine therapy. , 2001, Cancer research.

[24]  I. Bièche,et al.  Real-time reverse transcription-PCR assay for future management of ERBB2-based clinical applications. , 1999, Clinical chemistry.

[25]  M. Greenberg,et al.  Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor , 1999, Cell.

[26]  J. Hanley,et al.  The meaning and use of the area under a receiver operating characteristic (ROC) curve. , 1982, Radiology.

[27]  Zhen-hua Wang,et al.  FoxO 6 inhibits cell proliferation in lung carcinoma through up-regulation of USP 7 , 2015 .

[28]  Ryuji Kobayashi,et al.  IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. , 2004, Cell.

[29]  I. Bièche,et al.  Quantification of estrogen receptor alpha and beta expression in sporadic breast cancer. , 2001, Oncogene.