Mechanisms underlying differential expression of interleukin-8 in breast cancer cells

Abstract

We have recently reported that interleukin-8 (IL-8) expression was inversely correlated to estrogen receptor (ER) status and was overexpressed in invasive breast cancer cells. In the present study, we show that IL-8 overexpression in breast cancer cells involves a higher transcriptional activity of IL-8 gene promoter. Cloning of IL-8 promoter from MDA-MB-231 and MCF-7 cells expressing high and low levels of IL-8, respectively, shows the integrity of the promoter in both cell lines. Deletion and site-directed mutagenesis of the promoter demonstrate that NF-jB and AP-1 and to a lesser extent C/EBP binding sites play a crucial role in the control of IL-8 promoter activity in MDA-MB-231 cells. Knockdown of NF-jB and AP-1 activities by adenovirusmediated expression of an NF-jB super-repressor and RNA interference, respectively, decreased IL-8 expression in MDA-MB-231 cells. On the contrary, restoration of Fra-1, Fra-2, c-Jun, p50, p65, C/EBPa and C/EBPb expression levels in MCF-7 cells led to a promoter activity comparable to that observed in MDA-MB-231 cells. Our data constitute the first extensive study of IL-8 gene overexpression in breast cancer cells and suggest that the high expression of IL-8 in invasive cancer cells requires a complex cooperation between NF-jB, AP-1 and C/EBP transcription factors.

Berberine hydrochloride IL-8 dependently inhibits invasion and IL-8-independently promotes cell apoptosis in MDA-MB-231 cells

“…Therefore, chemotherapeutic agents with an inhibitory effect on IL-8 production may be more efficacious in treating breast cancer. MDA-MB-231 is one of the breast cancer cell lines constitutively expressing a high level of IL-8 (15,16). Consistent with previous studies (41), IL-8 enhanced the invasive ability of MDA-MB-231 cells in our experiments ( Fig.…”

“…Findings of recent studies have shown that the overexpression of IL-8 is associated with recurrence and poor prognosis in breast cancer (11)(12)(13)(14). The expression of IL-8 in highly metastatic breast cancer MDA-MB-231 cells is much higher than that in the non-metastatic MCF-7 breast cancer cell line (15,16). Recent studies have demonstrated that, during or after treatment, several chemotherapeutic drugs resulted in resistance and cancer metastasis associated with upregulated IL-8 in human breast cancer (17)(18)(19)(20).…”

Cell- and gene-specific regulation of primary target genes by the androgen receptor

“…Indeed, several of the identified sequence motifs appear from other studies to be functional. For example, our computational analysis revealed an AP-1 binding motif at ARE4.13 of the interleukin-8 (IL8) gene, which Freund et al (2004) showed to be important for AP-1-mediated transcriptional regulation of IL8 promoter expression. We suggest that many AREs are likely composite elements, and that regulatory cross-talk at AREs may typically modulate transcription of ARGs.…”

NF-κB activation in inflammatory breast cancer is associated with oestrogen receptor downregulation, secondary to EGFR and/or ErbB2 overexpression and MAPK hyperactivation

“…This inhibitory cross-talk can be appreciated from the fact that an increase in both NF-kB DNA-binding activity (Nakshatri et al, 1997;Pratt et al, 2003) and expression of NF-kB target genes like IL8 (Freund et al, 2004) coincides with a shift from oestrogen dependence to oestrogen independence in breast cancer. The inverse correlation between ER and NF-kB activity is further supported by the fact that some breast tumours, resistant to the tumoricidal effect of antiestrogens, become sensitised to apoptosis and show a reduction in NF-kB activity after treatment with oestrogen (Jordan, 2004).…”