A cluster of noncoding RNAs activates the ESR1 locus during breast cancer adaptation.
Estrogen receptor-α (ER)-positive breast cancer cells undergo hormone-independent proliferation after deprivation of oestrogen, leading to endocrine therapy resistance. Up-regulation of the ER gene (ESR1) is critical for this process, but the underlying mechanisms remain unclear. Here we show that the combination of transcriptome and fluorescence in situ hybridization analyses revealed that oestrogen deprivation induced a cluster of noncoding RNAs that defined a large chromatin domain containing the ESR1 locus. We termed these RNAs as Eleanors (ESR1 locus enhancing and activating noncoding RNAs). Eleanors were present in ER-positive breast cancer tissues and localized at the transcriptionally active ESR1 locus to form RNA foci. Depletion of one Eleanor, upstream (u)-Eleanor, impaired cell growth and transcription of intragenic Eleanors and ESR1 mRNA, indicating that Eleanors cis-activate the ESR1 gene. Eleanor-mediated gene activation represents a new type of locus control mechanism and plays an essential role in the adaptation of breast cancer cells.
Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.|Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Saori
S
Tomita
Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
Mohamed Osama Ali
MOA
Abdalla
Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.|Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Saori
S
Fujiwara
Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
Haruka
H
Matsumori
Department of Advanced Initiative Medicine, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan.
Kazumitsu
K
Maehara
Department of Advanced Initiative Medicine, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan.
Yasuyuki
Y
Ohkawa
Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Hirotaka
H
Iwase
Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
Noriko
N
Saitoh
Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.|Program for Leading Graduate Schools 'HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program', Kumamoto University, Kumamoto 860-8556, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo 102-0076, Japan.
Mitsuyoshi
M
Nakao
D000222:Adaptation, Physiological; D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D061986:MCF-7 Cells; D008969:Molecular Sequence Data; D022661:RNA, Untranslated / Q000378:metabolism*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D022661:RNA, Untranslated; D013267:Stilbenes; D000077185:Resveratrol