Abstract Background: 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 also overexpress Interleukin 6 (IL-6), a pro-inflammatory cytokine that stimulates the growth of breast cancer stem/ progenitor cells. Results: Here 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 (ERa) promoter and the loss of ERa mRNA expression. Finally, IL-6 induces the methylation of IL-6 distal promoter and of CD133 promoter region 2, which harbour putative repressor regions. Conclusion: We 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.

Epigenetic control of the basal-like gene expression profile via Interleukin-6 in breast cancer cells.

D'ANELLO, LAURA;SANSONE, PASQUALE;STORCI, GIANLUCA;MITRUGNO, VALENTINA MARIA;D'UVA, GABRIELE MATTEO;CHIECO, PASQUALE;BONAFE', MASSIMILIANO
2010

Abstract

Abstract Background: 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 also overexpress Interleukin 6 (IL-6), a pro-inflammatory cytokine that stimulates the growth of breast cancer stem/ progenitor cells. Results: Here 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 (ERa) promoter and the loss of ERa mRNA expression. Finally, IL-6 induces the methylation of IL-6 distal promoter and of CD133 promoter region 2, which harbour putative repressor regions. Conclusion: We 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.
D'Anello L.; Sansone P.; Storci G.; Mitrugno V.; D'Uva G.; Chieco P.; Bonafé M.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/97650
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