Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors.
The DNA-binding sites of estrogen receptor α (ERα) show great plasticity under the control of hormones and endocrine therapy. Tamoxifen is a widely applied therapy in breast cancer that affects ERα interactions with coregulators and shifts the DNA-binding signature of ERα upon prolonged exposure in breast cancer. Although tamoxifen inhibits the progression of breast cancer, it increases the risk of endometrial cancer in postmenopausal women. We therefore asked whether the DNA-binding signature of ERα differs between endometrial tumors that arise in the presence or absence of tamoxifen, indicating divergent enhancer activity for tumors that develop in different endocrine milieus. Using ChIP sequencing (ChIP-seq), we compared the ERα profiles of 10 endometrial tumors from tamoxifen users with those of six endometrial tumors from nonusers and integrated these results with the transcriptomic data of 47 endometrial tumors from tamoxifen users and 64 endometrial tumors from nonusers. The ERα-binding sites in tamoxifen-associated endometrial tumors differed from those in the tumors from nonusers and had distinct underlying DNA sequences and divergent enhancer activity as marked by histone 3 containing the acetylated lysine 27 (H3K27ac). Because tamoxifen acts as an agonist in the postmenopausal endometrium, similar to estrogen in the breast, we compared ERα sites in tamoxifen-associated endometrial cancers with publicly available ERα ChIP-seq data in breast tumors and found a striking resemblance in the ERα patterns of the two tissue types. Our study highlights the divergence between endometrial tumors that arise in different hormonal conditions and shows that ERα enhancer use in human cancer differs in the presence of nonphysiological endocrine stimuli.
Department of Molecular Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Marjolein
M
Droog
Department of Molecular Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.|Department of Molecular Carcinogenesis, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Ekaterina
E
Nevedomskaya
Department of Molecular Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Gwen M
GM
Dackus
Department of Molecular Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Renske
R
Fles
Department of Molecular Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.|Department of Molecular Carcinogenesis, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Yongsoo
Y
Kim
Department of Pathology, University of Groningen, 9700 RB Groningen, The Netherlands.
Harry
H
Hollema
Department of Gynecological Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
Marian J
MJ
Mourits
Department of Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Petra M
PM
Nederlof
Department of Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Hester H
HH
van Boven
Department of Molecular Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.|Department of Medical Oncology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Sabine C
SC
Linn
Department of Epidemiology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Flora E
FE
van Leeuwen
Department of Molecular Carcinogenesis, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.|Faculty of Electrical Engineering, Mathematics, and Computer Science, Delft University of Technology, 2628 CD, Delft, The Netherlands.
Lodewyk F A
LF
Wessels
Department of Molecular Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; w.zwart@nki.nl.
Wilbert
W
Zwart
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D013629:Tamoxifen / Q000627:therapeutic use*; D059467:Transcriptome / Q000187:drug effects
D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D013629:Tamoxifen
ChIP-seq; breast cancer; endometrial cancer; estrogen receptor; tamoxifen