TY - JOUR
T1 - Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer
AU - Magnani, Luca
AU - Stoeck, Alexander
AU - Zhang, Xiaoyang
AU - Lánczky, András
AU - Mirabella, Anne C.
AU - Wang, Tian Li
AU - Gyorffy, Balázs
AU - Lupien, Mathieu
PY - 2013/4/16
Y1 - 2013/4/16
N2 - 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.
AB - 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.
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U2 - 10.1073/pnas.1219992110
DO - 10.1073/pnas.1219992110
M3 - Article
C2 - 23576735
AN - SCOPUS:84876204394
VL - 110
SP - E1490-E1499
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 16
ER -