Abstract
BackgroundBasal-like carcinoma are aggressive breast cancers that frequently carry p53 inactivating mutations, lack estrogen receptor-α (ERα) and express the cancer stem cell markers CD133 and CD44. These tumors also over-express Interleukin 6 (IL-6), a pro-inflammatory cytokine that stimulates the growth of breast cancer stem/progenitor cells.ResultsHere we show that p53 deficiency in breast cancer cells induces a loss of methylation at IL-6 proximal promoter region, which is maintained by an IL-6 autocrine loop. IL-6 also elicits the loss of methylation at the CD133 promoter region 1 and of CD44 proximal promoter, enhancing CD133 and CD44 gene transcription. In parallel, IL-6 induces the methylation of estrogen receptor (ERα) promoter and the loss of ERα mRNA expression. Finally, IL-6 induces the methylation of IL-6 distal promoter and of CD133 promoter region 2, which harbour putative repressor regions.ConclusionWe conclude that IL-6, whose methylation-dependent autocrine loop is triggered by the inactivation of p53, induces an epigenetic reprogramming that drives breast carcinoma cells towards a basal-like/stem cell-like gene expression profile.
Highlights
Basal-like carcinoma are aggressive breast cancers that frequently carry p53 inactivating mutations, lack estrogen receptor-a (ERa) and express the cancer stem cell markers CD133 and CD44
Interleukin 6 (IL-6) induces the methylation of IL-6 distal promoter and of CD133 promoter region 2, which contain putative repressor binding sites
Reduced IL-6 proximal promoter methylation and high IL-6 expression in breast cancer cells carrying inactivated p53 In keeping with previous observations [5,31], significantly higher IL-6 mRNA and secreted IL-6 protein levels were found in MDA-MB231 cells [5] compared to p53 wild type MCF-7 cells (Figure 1A)
Summary
Basal-like carcinoma are aggressive breast cancers that frequently carry p53 inactivating mutations, lack estrogen receptor-a (ERa) and express the cancer stem cell markers CD133 and CD44. These tumors overexpress Interleukin 6 (IL-6), a pro-inflammatory cytokine that stimulates the growth of breast cancer stem/ progenitor cells. Basal-like tumors are aggressive estrogen receptor-a (ERa) negative breast carcinomas that have been identified due to their peculiar gene expression profile [1,2,3] Such tumors display a stem cell-like gene expression profile, including the over-expression of cancer stem cells (CSCs) markers, such as CD133 [1,4] and CD44 [5,6,7,8,9]. Basal-like tumors over-express the proinflammatory cytokine Interleukin-6 (IL-6), a potent growth factor for breast cancer cells that enhances
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