Amplification of distant estrogen response elements deregulates target genes associated with tamoxifen resistance in breast cancer.
A causal role of gene amplification in tumorigenesis is well known, whereas amplification of DNA regulatory elements as an oncogenic driver remains unclear. In this study, we integrated next-generation sequencing approaches to map distant estrogen response elements (DEREs) that remotely control the transcription of target genes through chromatin proximity. Two densely mapped DERE regions located on chromosomes 17q23 and 20q13 were frequently amplified in estrogen receptor-α-positive luminal breast cancer. These aberrantly amplified DEREs deregulated target gene expression potentially linked to cancer development and tamoxifen resistance. Progressive accumulation of DERE copies was observed in normal breast progenitor cells chronically exposed to estrogenic chemicals. These findings may extend to other DNA regulatory elements, the amplification of which can profoundly alter target transcriptome during tumorigenesis.
Department of Molecular Medicine/Institute of Biotechnology, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
Pei-Yin
PY
Hsu
Hang-Kai
HK
Hsu
Xun
X
Lan
Liran
L
Juan
Pearlly S
PS
Yan
Jadwiga
J
Labanowska
Nyla
N
Heerema
Tzu-Hung
TH
Hsiao
Yu-Chiao
YC
Chiu
Yidong
Y
Chen
Yunlong
Y
Liu
Lang
L
Li
Rong
R
Li
Ian M
IM
Thompson
Kenneth P
KP
Nephew
Zelton D
ZD
Sharp
Nameer B
NB
Kirma
Victor X
VX
Jin
Tim H-M
TH
Huang
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D020218:Response Elements; D013629:Tamoxifen / Q000494:pharmacology*
D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D004967:Estrogens; D013629:Tamoxifen