Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression profile of the endocrine therapy resistant breast cancer cells LTED depleted of PBX1 or treated with the gamma-secretase inhibitor MRK003

ABSTRACT: Analysis of the response to PBX1 deprivation either using an siRNA approach or using a chemicalcompound indirectly targeting it. Deprivation of PBX1 is hypothesized to be essential for the growth of endocrine therapy resistant breast cancer cells (LTED) Total RNA was obtained from cells treated with siPBX1 or a control siRNA. The second set contains RNA from cells treated with MRK003 or a control (DMSO).

ORGANISM(S): Homo sapiens

SUBMITTER: luca magnani

PROVIDER: E-GEOD-36928 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer.

Magnani Luca L Stoeck Alexander A Zhang Xiaoyang X Lánczky András A Mirabella Anne C AC Wang Tian-Li TL Gyorffy Balázs B Lupien Mathieu M

Proceedings of the National Academy of Sciences of the United States of America 20130401 16

The estrogen receptor (ER)α drives growth in two-thirds of all breast cancers. Several targeted therapies, collectively termed endocrine therapy, impinge on estrogen-induced ERα activation to block tumor growth. However, half of ERα-positive breast cancers are tolerant or acquire resistance to endocrine therapy. We demonstrate that genome-wide reprogramming of the chromatin landscape, defined by epigenomic maps for regulatory elements or transcriptional activation and chromatin openness, underli ...[more]

PMID: 23576735

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Project description: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

Dataset Information

Expression profile of the endocrine therapy resistant breast cancer cells LTED depleted of PBX1 or treated with the gamma-secretase inhibitor MRK003

Publications

Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer.

Similar Datasets

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