Loss of estrogen receptor signaling triggers epigenetic silencing of downstream targets in breast cancer.
Alterations in histones, chromatin-related proteins, and DNA methylation contribute to transcriptional silencing in cancer, but the sequence of these molecular events is not well understood. Here we demonstrate that on disruption of estrogen receptor (ER) alpha signaling by small interfering RNA, polycomb repressors and histone deacetylases are recruited to initiate stable repression of the progesterone receptor (PR) gene, a known ERalpha target, in breast cancer cells. The event is accompanied by acquired DNA methylation of the PR promoter, leaving a stable mark that can be inherited by cancer cell progeny. Reestablishing ERalpha signaling alone was not sufficient to reactivate the PR gene; reactivation of the PR gene also requires DNA demethylation. Methylation microarray analysis further showed that progressive DNA methylation occurs in multiple ERalpha targets in breast cancer genomes. The results imply, for the first time, the significance of epigenetic regulation on ERalpha target genes, providing new direction for research in this classical signaling pathway.
Leu
Yu-Wei
YW
Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
Yan
Pearlly S
PS
Fan
Meiyun
M
Jin
Victor X
VX
Liu
Joseph C
JC
Curran
Edward M
EM
Welshons
Wade V
WV
Wei
Susan H
SH
Davuluri
Ramana V
RV
Plass
Christoph
C
Nephew
Kenneth P
KP
Huang
Tim H-M
TH
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D017931:DNA Primers; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D006801:Humans; D034622:RNA Interference; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D017931:DNA Primers; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone