Genomics

Dataset Information

298

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


ABSTRACT: The estrogen receptor alpha (ERa) drives the growth of two-thirds of all breast cancers. Endocrine therapy impinges on estrogen-induced ERa activation to block tumor growth. However, half of ERa-positive breast cancers are tolerant or acquire endocrine therapy resistance. Here we demonstrate that breast cancer cells undergo genome-wide reprogramming of their chromatin landscape, defined by epigenomic maps and chromatin openness, as they acquire resistance to endocrine therapy. This reveals a role for the Notch pathway while excluding classical ERa signaling. In agreement, blocking Notch signaling, using gamma-secretase inhibitors, or targeting its downstream gene PBX1 abrogates growth of endocrine therapy-resistant breast cancer cells. Moreover Notch signaling through PBX1 directs a transcriptional program predictive of tumor outcome and endocrine therapy response. Comparing histone modifications (H3K4me2 and H3K36me3), chromatin openness (FAIRE) and PBX1 binding between endocrine therapy sensitive MCF7 and resistant MCF7-LTED cells.

ORGANISM(S): Homo sapiens  

SUBMITTER: xiaoyang zhang   Xiaoyang Zhang 

PROVIDER: E-GEOD-37323 | ArrayExpress | 2013-05-01

SECONDARY ACCESSION(S): GSE37323SRP012270PRJNA159579

REPOSITORIES: GEO, ArrayExpress, ENA

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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]

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