Unknown,Transcriptomics,Genomics,Proteomics

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Estrogen deprivation alters epigenetic modifications in breast cancer cells - HOXC10 loss in endocrine resistance


ABSTRACT: Postmenopausal breast cancer patients benefit from aromatase inhibitors (AIs) that reduce the levels of estrogens critical for the growth of estrogen receptor (ER)-positive tumors. Unfortunately, many tumors are resistant to AI, and we are only beginning to understand the complex mechanisms underlying treatment resistance. Here we set out to determine whether epigenetic changes could contribute to therapy resistance. For AI-resistance models, we used previously established MCF-7 cell clones, termed C4-12 and long-term estrogen deprivation (LTED), that were isolated after being cultured in estrogen-free media for 9 months and 18M-bM-^@M-^S24 months, respectively. Methyl CpG Binding Domain (MBD) - pull down followed by affymetrix promoter array was used to detect promoter methylation patterns in these cell lines. These studies identified widespread genomic hyper- and hypomethylation events, with a significant enrichment of promoter hypermethylation of development-associated genes in both cell lines. A developmentally regulated gene that was heavily methylated and lost expression in both cell-line systems was HOXC10. Moreover, we found that HOXC10 is an estrogen-regulated gene and lack of ER regulation is associated with progressive epigenetic silencing through EZH2/H3K27me3 and DNA hypermethylation. Stable knockdown of HOXC10 in MCF-7 cells resulted in increased cell growth, reduced cell apoptosis, and increased cell motility. A preliminary study using AI-treated breast tumors did not show significant associations, however, the numbers were small. We identified HOXC10 methylation as a novel determinant of endocrine resistance. Also, we revealed that epigenetic reprogramming of genes involved in development may be a fundamental phenomenon in hormone resistance. Therefore, our study might provide the basis for the expansion of clinical markers for endocrine resistance and future clinical trials such as combination of endocrine and epigenetic therapies. Long-term estrogen deprived previously established MCF-7 cell clones termed C4-12 and LTED genomic DNA subjected to Methyl CpG Binding Domain (MBD) - pull down followed by affymetrix promoter array to detect promoter methylation patterns

ORGANISM(S): Homo sapiens

SUBMITTER: Yuanxin Xi 

PROVIDER: E-GEOD-39783 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Resistance to aromatase inhibitors (AIs) is a major clinical problem in the treatment of estrogen receptor (ER)-positive breast cancer. In two breast cancer cell line models of AI resistance, we identified widespread DNA hyper- and hypomethylation, with enrichment for promoter hypermethylation of developmental genes. For the homeobox gene HOXC10, methylation occurred in a CpG shore, which overlapped with a functional ER binding site, causing repression of HOXC10 expression. Although short-term b  ...[more]

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