Atypical methylation of the interleukin-8 gene correlates strongly with the metastatic potential of breast carcinoma cells

Abstract

Previously, we have shown that a strong correlation exists between the metastatic potential of breast carcinoma cell lines and their ectopic expression of IL-8. The undifferentiated, highly metastatic cell lines with high metastatic potential produce much more IL-8 than their differentiated lower metastatic counterparts. After eliminating the possibility that transcription factor activity was responsible for differences in IL-8 release, we examined the IL-8 gene for possible epigenetic modifications. Here, we report an aberrant methylation pattern that may be responsible for the differences in IL-8 release between the high and low metastatic cell lines. We determined that none of the deoxycytidylate-phosphatedeoxyguanylate (CpG) sites in the reported IL-8 promoter were methylated in either cell type. Much further upstream in the IL-8 gene, two CpG sites were identified that are differentially methylated. These two sites were fully methylated in the high metastatic cell lines, which produce large quantities of IL-8 and remain unmethylated in the low metastatic cell lines where the IL-8 gene is relatively silent. The DNA methylation results presented here differ from the common epigenetic paradigm in which methylation of promoter CpG islands silences gene expression, suggesting that there are additional epigenetic control mechanisms that as yet have not been fully appreciated or explored.

Increased Serum Interleukin-8 in Patients with Early and Metastatic Breast Cancer Correlates with Early Dissemination and Survival

“…This observation renders clinical support to the observations made by De Larco et al (38,39). It is reasonable to equate the presence of disseminated tumor cells in bone marrow as the precursor of actual bone metastases.…”

“…De Larco et al (38) showed a strong correlation between the metastatic potential of breast carcinoma cell lines and their ectopic expression of IL-8. They continued to show that increased IL-8 expression in metastasis-prone cell lines is possibly caused by an atypical epigenetic mechanism, whereby upstream CpG methylation, rather than promoter methylation, results in increased IL-8 production (39). More recent data have suggested that IL-8 plays a major role in the predilection of breast cancer for metastasis to bone and that IL-8 expression in breast cancer relates to estrogen receptor negativity (40,41).…”

Increased NOS2 predicts poor survival in estrogen receptor–negative breast cancer patients

“…IL-8 is preferentially expressed by ER-negative breast tumors and breast cancer cell lines (34). Atypical methylation of the IL8 gene is a candidate mechanism for the differential expression of IL-8 in breast tumors (52). Regulation of IL-8 expression by NO has previously been observed in pancreatic cancer cells,…”

Epigenetic modification of retinoic acid-treated human embryonic stem cells

“…The data further suggest that methylation of CpG sites is required for a cell to express high levels of RARB when induced by RA. There is also additional evidence that DNA hypermethylation in specific regions (promoter or genebody) can lead to upregulation of transcription (34,35).…”