Correction: FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer.

In the published version of this article, the images for cytoplasmic and nuclear FGF7 in MDA-MB-231 cells were duplicated and mistaken for total FGF7 in SKBR-3 and MDA-MB-231 cells.

FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer.

Vascular endothelial growth factor (VEGF) has a central role in breast cancer development and progression, but the mechanisms that control its expression are poorly understood. Breast cancer tissue microarrays revealed an inverse correlation between the Forkhead transcription factor Forkhead box class O (FOXO)3a and VEGF expression. Using the lapatinib-sensitive breast cancer cell lines BT474 and SKBR3 as model systems, we tested the possibility that VEGF expression is negatively regulated by FOXO3a. Lapatinib treatment of BT474 or SKBR3 cells resulted in nuclear translocation and activation of FOXO3a, followed by a reduction in VEGF expression. Transient transfection and inducible expression experiments showed that FOXO3a represses the proximal VEGF promoter, whereas another Forkhead member, FOXM1, induces VEGF expression. Chromatin immunoprecipitation and oligonucleotide pull-down assays showed that both FOXO3a and FOXM1 bind a consensus Forkhead response element (FHRE) in the VEGF promoter. Upon lapatinib stimulation, activated FOXO3a displaces FOXM1 bound to the FHRE before recruiting histone deacetylase 2 (HDAC2) to the promoter, leading to decreased histones H3 and H4 acetylation, and concomitant transcriptional inhibition of VEGF. These results show that FOXO3a-dependent repression of target genes in breast cancer cells, such as VEGF, involves competitive displacement of DNA-bound FOXM1 and active recruitment of transcriptional repressor complexes.

Regulation of the FOXM1 transcription factor by the estrogen receptor alpha at the protein level, in breast cancer.

Breast cancer is the most frequent type of cancer of women in the western world. Antiestrogens, including Tamoxifen (OHT) and Faslodex (ICI), are widely used in the endocrine treatment of breast cancer. However, the majority of breast cancers are either resistant to endocrine therapy or eventually become unresponsive to antiestrogen therapy. Better understanding of the molecular mechanisms that govern tumour proliferation, is therefore needed to develop new therapies for the disease. The Forkhead family of transcription factors plays an important role in regulating cell proliferation, cell death and differentiation.The estrogen receptor (ER) a positive breast carcinoma cell line MCF-7 and the ERa negative line MDA-MB-231 was used to study the potential regulation of the Forkhead member FOXM1 by ER. It was indicated that estrogen and ER regulate the expression of FOXM1 at the protein level. Since Forkhead proteins play an important role in regulating cell proliferation, cell death and differentiation, this study helps to explain some of the functions of ER in tumourigenesis, and the way these Forkhead proteins could be crucial targets for therapeutic strategies and/or markers for diagnosis and prognosis.