title: Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer.
abstract: 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, 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 epigenetically 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.
authors.affiliation: Norris Cotton Cancer Center, Geisel School of Medicine, Dartmouth College, Lebanon, NH 03756, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Magnani
authors.forename: Alexander
authors.initials: A
authors.lastname: Stoeck
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Zhang
authors.forename: András
authors.initials: A
authors.lastname: Lánczky
authors.forename: Anne C
authors.initials: AC
authors.lastname: Mirabella
authors.forename: Tian-Li
authors.initials: TL
authors.lastname: Wang
authors.forename: Balázs
authors.initials: B
authors.lastname: Gyorffy
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lupien
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic / Q000235:genetics / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D053263:Gene Regulatory Networks / Q000235:genetics / Q000502:physiology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D046228:Microarray Analysis; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D047628:Estrogen Receptor alpha; D051880:Receptors, Notch