Transrepression of the estrogen receptor promoter by calcitriol in human breast cancer cells via two negative vitamin D response elements

Swami, Srilatha; Krishnan, Aruna V.; Peng, Linfeng; Lundqvist, Johan; Feldman, David

doi:10.1530/erc-12-0281

Cited by 42 publications

(31 citation statements)

References 38 publications

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“…Calcitriol has also been shown to modulate the transcription by interacting with either the positive or negative VD response element (VDRE) of the promoters of target genes [11]. For example, VDR agonists were previously reported to down-regulate the expression of estrogen receptor (ER) α, which has two potential negative VDREs in the promoter, through a VDR-dependent mechanism in ER-negative breast cancer cells [12,13]. A genome-wide investigation by RNA-Seq technology and The Cancer Genome Atlas identified the transcriptional targets of calcitriol in breast cancer cells [14,15].…”

Section: Introductionmentioning

confidence: 99%

Down-Regulation of Ca2+-Activated K+ Channel KCa1.1 in Human Breast Cancer MDA-MB-453 Cells Treated with Vitamin D Receptor Agonists

Khatun

Fujimoto

Kurihara

et al. 2016

IJMS

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Vitamin D (VD) reduces the risk of breast cancer and improves disease prognoses. Potential VD analogs are being developed as therapeutic agents for breast cancer treatments. The large-conductance Ca2+-activated K+ channel KCa1.1 regulates intracellular Ca2+ signaling pathways and is associated with high grade tumors and poor prognoses. In the present study, we examined the effects of treatments with VD receptor (VDR) agonists on the expression and activity of KCa1.1 in human breast cancer MDA-MB-453 cells using real-time PCR, Western blotting, flow cytometry, and voltage-sensitive dye imaging. Treatments with VDR agonists for 72 h markedly decreased the expression levels of KCa1.1 transcripts and proteins in MDA-MB-453 cells, resulting in the significant inhibition of depolarization responses induced by paxilline, a specific KCa1.1 blocker. The specific proteasome inhibitor MG132 suppressed VDR agonist-induced decreases in KCa1.1 protein expression. These results suggest that KCa1.1 is a new downstream target of VDR signaling and the down-regulation of KCa1.1 through the transcriptional repression of KCa1.1 and enhancement of KCa1.1 protein degradation contribute, at least partly, to the antiproliferative effects of VDR agonists in breast cancer cells.

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Section: Introductionmentioning

confidence: 99%

Down-Regulation of Ca2+-Activated K+ Channel KCa1.1 in Human Breast Cancer MDA-MB-453 Cells Treated with Vitamin D Receptor Agonists

Khatun

Fujimoto

Kurihara

et al. 2016

IJMS

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“…Furthermore, 1α,25-dihydroxyvitamin D 3 and analogs have been reported to alter sex hormone signaling by suppressing the expression of estrogen receptor α [72][73][74][75][76][77] . It has also been reported that vitamin D deficiency alters reproductive functions in both male and female rats, indicating that vitamin D may affect sex hormone signaling 78,79 .…”

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confidence: 99%

Vitamin D as a regulator of steroidogenic enzymes

Lundqvist

2014

F1000Res

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During the last decades, the outlook on vitamin D has widened, from being a vitamin solely involved in bone metabolism and calcium homeostasis, to being a multifunctional hormone known to affect a broad range of physiological processes. The aim of this review is to summarize the research on vitamin D as a regulator of steroidogenic enzymes. Steroid hormones exert a wide range of physiological responses, including functions in the immune system, protein and carbohydrate metabolism, water and salt balance, reproductive system and development of sexual characteristics. The balance of sex hormones is also of importance in the context of breast and prostate cancer. Steroid hormones are synthesized in steroidogenic tissues such as the adrenal cortex, breast, ovaries, prostate and testis, either from cholesterol or from steroidogenic precursors secreted from other steroidogenic tissues. The hormonally active form of vitamin D has been reported to act as a regulator of a number of enzymes involved in the regulation of steroid hormon production, and thereby the production of both adrenal steroid hormones and sex hormones. The research reviewed in the article has in large part been performed in cell culture based experiments and laboratory animal experiments, and the physiological role of the vitamin D mediated regulation of steroidogenic enzyme need to be further investigated.

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“…This example very nicely demonstrates that application of formal criteria without overall weight of evidence assessment might result in misinterpretations. The effects on aromatase activity expression have been observed in breast cancer cells in vitro [37,39,40] and in immunocompromised mice bearing MCF-7 xenografts [41]. The latter study was not regarded for the classification due to the artificial situation generated in mice.…”

Section: Discussionmentioning

confidence: 99%

“…Besides the interaction with the parathormone system the Vit-D3 metabolite 1,25-Dihydroxyvitamin D3 has been shown to act as selective aromatase modulator, decreasing aromatase expression in breast cancer cells and the breast adipose tissue surrounding a breast tumour, resulting in a reduction of the local production of estrogens within the breast. Additionally, 1,25-dihydroxyvitamin D3 also represses estrogen receptor expression in breast cancer cells in vitro, two mechanisms possibly relevant for breast cancer therapy [37]. For the sake of this screening activity this publication was taken as in vitro evidence for an EATS-mediated MoA.…”

Section: -14]mentioning

confidence: 99%

Case study with natural substances on the various options to identify and categorise endocrine disruptors

Schuhmacher-Wolz¹,

Voss²,

Schneider³

2017

J Toxicol Health

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Background: Substances with endocrine disrupting properties are under special consideration in European Union regulations. In 2014 the European Commission published a roadmap which presented four possible options for identifying endocrine disruptors (ED). A further option was proposed by the chemical and crop protection industry. Methods: This case study investigated how natural substances (genistein, caffeine, vitamin D3, sucrose) would possibly be classified under these different options when the focus is on EATS (estrogenic, androgenic, thyroid and steroidogenic) mediated effects on basis of published data. Results: For sucrose no evidence for endocrine disrupting activity could be identified. The phytoestrogen genistein as well as caffeine would possibly be classified as ED, but caffeine only if potency is not regarded. Vitamin D3 does not elicit EATS mediated adverse effects in vivo. Conclusion: This screening approach reveals that substances for which safe use in humans is known from decades of experience might possibly be classified as endocrine disruptors with yet unknown regulatory consequences. The examples show that additional criteria beyond the WHO/IPCS definition for ED might be critical for the final classification of a substance as ED.

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Transrepression of the estrogen receptor promoter by calcitriol in human breast cancer cells via two negative vitamin D response elements

Cited by 42 publications

References 38 publications

Down-Regulation of Ca2+-Activated K+ Channel KCa1.1 in Human Breast Cancer MDA-MB-453 Cells Treated with Vitamin D Receptor Agonists

Down-Regulation of Ca2+-Activated K+ Channel KCa1.1 in Human Breast Cancer MDA-MB-453 Cells Treated with Vitamin D Receptor Agonists

Vitamin D as a regulator of steroidogenic enzymes

Case study with natural substances on the various options to identify and categorise endocrine disruptors

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