Abstract
E2F6 is a member of the E2F family of transcription factors involved in regulation of a wide variety of genes through both activation and repression. E2F6 has been reported as overexpressed in breast cancers but whether or not this is important for tumor development is unclear. We first checked E2F6 expression in tumor cDNAs and the protein level in a range of breast cancer cell lines. RNA interference-mediated depletion was then used to assess the importance of E2F6 expression in cell lines with regard to cell cycle profile using fluorescence-activated cell sorting and a cell survival assay using (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The overexpression of E2F6 was confirmed in breast tumor cDNA samples and breast cancer cell lines. Depletion of E2F6 in the breast cancer cells reduced cell viability in MCF-7, T-47D, and MDA-MB-231 cells. There was little effect in the nontumor breast cell line MCF-10A. The deleterious effect on cancer cells was greater during replication stress, leading to an increase in the proportion of breast cancer cells with sub-G1 DNA content. These results suggest that E2F6 might be essential for the survival of breast cancer cells experiencing replication stress, and therefore it could be a target for combined therapy.
Highlights
The E2F genes encode a family of nine transcription factors with one or more conserved DNA binding domains
E2F6 expression is greater in breast cancer than normal tissue We tested the expression levels of E2F6 by qPCR on an array of 43 breast adenocarcinoma cDNAs and 5 normal breast cDNAs
Using primers common to all E2F6 transcript variants, high levels of cDNA were found in the tumor samples relative to the normal tissue
Summary
The E2F genes encode a family of nine transcription factors with one or more conserved DNA binding domains. They bind promoters as either homo- or heterodimers and target distinct and overlapping promoters to regulate gene expression (Trimarchi and Lees, 2002; Attwooll et al, 2004). The E2F family members have been shown to control the expression of genes implicated in DNA replication, DNA damage repair, cell fate, and mitosis (Trimarchi and Lees, 2002; Attwooll et al, 2004; Cam et al, 2004; Dimova and Dyson, 2005; Bieda et al, 2006; Buttitta and Edgar, 2007; McClellan and Slack, 2007; Zalmas et al, 2008; Chen et al, 2009). E2Fs are implicated in upregulating genes whose expression correlates with metastasis and poor prognosis in breast
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