The first decade of estrogen receptor cistromics in breast cancer

Flach, Koen D.; Zwart, Wilbert

doi:10.1530/joe-16-0003

Cited by 17 publications

(12 citation statements)

References 147 publications

(141 reference statements)

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“…The hormonal environment of the cell greatly influences this cistrome because estrogen activates ERα by binding its ligand-binding domain. Upon activation, ERα's structural conformation changes to interact with cofactors at the DNA (2) and to regulate a transcriptional program that drives cell proliferation (3). Hence, the hormonal environment modulates the ERα cistrome and thereby rewires downstream effects.…”

mentioning

confidence: 99%

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Droog

Nevedomskaya

Dackus

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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.E strogen receptor α (ERα) is a steroid hormone receptor that behaves as a transcription factor by interacting with the DNA. The DNA-binding profile (cistrome) of ERα is dependent on context and tissue type (1). The hormonal environment of the cell greatly influences this cistrome because estrogen activates ERα by binding its ligand-binding domain. Upon activation, ERα's structural conformation changes to interact with cofactors at the DNA (2) and to regulate a transcriptional program that drives cell proliferation (3). Hence, the hormonal environment modulates the ERα cistrome and thereby rewires downstream effects.Endocrine therapies, as exemplified by tamoxifen, manipulate the DNA-binding capacities of the steroid hormone receptor ERα. Tamoxifen, a small-molecule inhibitor that competes with estrogens to bind ERα, is a major endocrine agent used in treating ERα-positive breast cancer patients. Studies in the breast cancer cell line MCF-7 show that prolonged tamoxifen exposure shifts the ERα cistrome, which consequently changes gene expression (4-6).Tamoxifen is a well-known selective estrogen receptor modulator (SERM) with tissue-selective physiological action. Early reports on tamoxifen's effects on transplanted MCF-7 cells in athymic mice revealed decreased tumor c...

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confidence: 99%

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Droog

Nevedomskaya

Dackus

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The actions of steroid hormones in the endometrium are mediated by hormone-receptors via the classical mechanisms, although non-genomic and rapid signaling are also present (Groothuis et al, 2007 ; Zwart et al, 2011 ; Flach and Zwart, 2016 ; Hewitt et al, 2016 ). Estrogens and P control the menstrual cycle (Groothuis et al, 2007 ; Andersen and Ezcurra, 2014 ) and the endometrium during the window of implantation (WOI), occurring in the mid-luteal phase (Wang and Dey, 2006 ).…”

Section: Intracrinology In Peripheral Tissuesmentioning

confidence: 99%

Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery

et al. 2018

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Our understanding of the intracrine (or local) regulation of estrogen and other steroid synthesis and degradation expanded in the last decades, also thanks to recent technological advances in chromatography mass-spectrometry. Estrogen responsive tissues and organs are not passive receivers of the pool of steroids present in the blood but they can actively modify the intra-tissue steroid concentrations. This allows fine-tuning the exposure of responsive tissues and organs to estrogens and other steroids in order to best respond to the physiological needs of each specific organ. Deviations in such intracrine control can lead to unbalanced steroid hormone exposure and disturbances. Through a systematic bibliographic search on the expression of the intracrine enzymes in various tissues, this review gives an up-to-date view of the intracrine estrogen metabolisms, and to a lesser extent that of progestogens and androgens, in the lower female genital tract, including the physiological control of endometrial functions, receptivity, menopausal status and related pathological conditions. An overview of the intracrine regulation in extra gynecological tissues such as the lungs, gastrointestinal tract, brain, colon and bone is given. Current therapeutic approaches aimed at interfering with these metabolisms and future perspectives are discussed.

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“…Estrogen receptor α (ERα) and cAMP-responsive element binding protein 1 (CREB1) are two unrelated transcription factors that, at first sight, have nothing to do with each other. ERα is a member of the nuclear receptor superfamily; in response to binding its cognate ligand estrogen, it is activated as a transcription factor and binds as a homodimer to specific DNA sequences across the genome to regulate target genes ( Heldring et al, 2007 ; Flach & Zwart, 2016 ). CREB1 and other family members such as ATF1 contain a basic region for binding DNA followed by a leucine zipper for homo- or heterodimerization; as its name indicates, it is a paradigmatic target of the cAMP-activated PKA.…”

Section: Introductionmentioning

confidence: 99%

ERα activity depends on interaction and target site corecruitment with phosphorylated CREB1

et al. 2018

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The first decade of estrogen receptor cistromics in breast cancer

Cited by 17 publications

References 147 publications

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery

ERα activity depends on interaction and target site corecruitment with phosphorylated CREB1

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