Abstract |
In postmenopausal breast cancers, the increase in aromatase expression observed in tumour associated adipose stromal cells is mediated via the upregulation of promoter II (PII) transcription. Factors such as PGE₂ which are secreted from breast carcinomas induce PII expression. The orphan nuclear receptor LRH-1/NR5A2 is one of the critical downstream transcriptional mediators of this effect. The aim of the current study was to determine whether LRH-1 could bind directly to PII and whether the suppression of LRH-1 expression could inhibit aromatase expression in human adipose stromal fibroblasts. Chromatin immunoprecipitation demonstrated endogenous LRH-1 occupancy on PII under basal conditions and with treatment with forskolin and phorbol 12-myristate 13-acetate (PMA). To assess the impact of LRH-1 knockdown on FSK/PMA mediated PII expression, cells were transfected with shRNA targeted against LRH-1 (shLRH-1) and treated with forskolin and PMA. A decrease in LRH-1, PII and total aromatase mRNA transcripts was observed in shLRH-1 transfected cells compared to controls under basal and treatment conditions. The results of this study support the hypothesis that suppression of LRH-1 may potentially be beneficial in the tissue specific regulation of aromatase expression in post menopausal breast cancer.
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Authors | Ashwini L Chand, Kerrie A Herridge, Tamara L Howard, Evan R Simpson, Colin D Clyne |
Journal | Steroids
(Steroids)
Vol. 76
Issue 8
Pg. 741-4
(Jul 2011)
ISSN: 1878-5867 [Electronic] United States |
PMID | 21392518
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011 Elsevier Inc. All rights reserved. |
Chemical References |
- NR5A2 protein, human
- RNA, Small Interfering
- Receptors, Cytoplasmic and Nuclear
- Colforsin
- phorbolol myristate acetate
- Aromatase
- Dinoprostone
- Tetradecanoylphorbol Acetate
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Topics |
- Adipose Tissue
(enzymology)
- Aromatase
(genetics)
- Breast
(enzymology)
- Breast Neoplasms
(genetics)
- Chromatin Immunoprecipitation
- Colforsin
(pharmacology)
- Dinoprostone
(metabolism)
- Female
- Fibroblasts
(enzymology)
- Gene Expression Regulation, Enzymologic
- Gene Expression Regulation, Neoplastic
- Gene Knockout Techniques
- Humans
- Organ Specificity
- Postmenopause
(metabolism)
- Promoter Regions, Genetic
- RNA, Small Interfering
(genetics)
- Receptors, Cytoplasmic and Nuclear
(genetics, metabolism)
- Stromal Cells
(enzymology)
- Tetradecanoylphorbol Acetate
(analogs & derivatives, pharmacology)
- Transfection
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