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

Luca Magnani, Alexander Stoeck, Xiaoyang Zhang, András Lánczky, Anne C. Mirabella, Tian Li Wang, Balázs Gyorffy, Mathieu Lupien

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

The estrogen receptor (ER)α drives growth in two-thirds of all breast cancers. Several targeted therapies, collectively termed endocrine therapy, impingeonestrogen-induced ERα activationtoblock tumor growth. However, half ofERα-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, underlies resistance to endocrine therapy. This annotation reveals endocrine therapy-response specific regulatory networks where NOTCH pathway is overactivated in resistant breast cancer cells, whereas classical ERα signaling is epige-netically disengaged. Blocking NOTCH signaling abrogates growth of resistant breast cancer cells. Its activation state in primary breast tumors is a prognostic factor of resistance in endocrine treated patients. Overall, our work demonstrates that chromatin landscape reprogramming underlies changes in regulatory networks driving endocrine therapy resistance in breast cancer.

Original languageEnglish
Pages (from-to)E1490-E1499
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number16
DOIs
Publication statusPublished - Apr 16 2013

ASJC Scopus subject areas

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