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Oestrogenic and androgenic activity of triclosan in breast cancer cells. |
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Friday, 09 November 2007 |
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As a consequence of its widespread use as an antimicrobial agent in consumer goods, triclosan has become distributed ubiquitously across the ecosystem, and recent reports that it can cause endocrine disruption in aquatic species has increased concern. It is reported here that triclosan possesses intrinsic oestrogenic and androgenic activity in a range of assays in vitro which could provide some explanation for the endocrine disrupting properties described in aquatic populations. In terms of oestrogenic activity, triclosan displaced [(3)H]oestradiol from oestrogen receptors (ER) of MCF7 human breast cancer cells and from recombinant human ERalpha/ERbeta. Triclosan at 10(-5) m completely inhibited the induction of the oestrogen-responsive ERE-CAT reporter gene in MCF7 cells by 10(-10) m 17beta-oestradiol and the stimulation of growth of MCF7 human breast cancer cells by 10(-10) m 17beta-oestradiol. On its own, 1 microm triclosan increased the growth of MCF7 cells over 21 days. Triclosan also had androgenic activity. It displaced [(3)H]testosterone from binding to the ligand binding domain of the rat androgen receptor (AR). Triclosan was able to inhibit the induction of the androgen-responsive LTR-CAT reporter gene in S115 mouse mammary tumour cells by 10(-9) m testosterone and in T47D human breast cancer cells by 10(-8) m testosterone at concentrations of 10(-7) m and 10(-6) m, respectively. Triclosan at 2 x 10(-5) m antagonized the stimulation of the growth of S115+A mouse mammary tumour cells by 10(-9) m testosterone. The finding that triclosan has oestrogenic and androgenic activity warrants further investigation in relation to both endocrine disruption of aquatic wildlife and any possible impact on human health. Copyright (c) 2007 John Wiley & Sons, Ltd.
Authors:RH Gee, A Charles, N Taylor, PD Darbre
Keywords:breast cancer cells, human breast cancer, tumour cells, triclosan, endocrine disruption, testosterone, oestrogen receptors, microm, androgenic, reporter gene, androgen, induction, displaced
Source:Pubmed
Affiliates:School of Biological Sciences, The University of Reading, Reading, RG6 6AJ, UK. |
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Testosterone upregulation of tissue type plasminogen activator expression in Sertoli cells : tPA expression in Sertoli cells. |
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Friday, 09 November 2007 |
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Our previous studies have demonstrated that tissue type plasminogen activator (tPA) might be involved in matrix degradation of blood-testis barrier in rat. In this study, we have further investigated the effect of testosterone (T) on tPA production in rat Sertoli cells. Our results showed that Sertoli cells isolated from rat testes at various ages in vitro secreted tPA in an age-dependent manner. The tPA activity was detected on day 20 after birth, and reached maximum on day 60. The Sertoli cells isolated from the testes on day 20 were then cultured in the presence or absence of testosterone, FSH, and forskolin, the tPA activities were upregulated by T, FSH and forskolin. Addition of H89 or U0126, both inhibited the testosterone-, FSH-, and forskolin-induced tPA expression. It is suggested that FSH- and testosterone-stimulated tPA expression in Sertoli cells may be via PKA and ERK signal transduction. Furthermore, we have observed that testosterone stimulated tPA secretion at all the stages of spermatogenesis (II-VI, VII-VIII, IX-XII and XIII-I), the highest stimulation of tPA activity was observed at stages VII-VIII. This study further suggests that testosterone-induced tPA activity in the Sertoli cells might be related to the function of blood-testis barrier opening and/or closing.
Authors:J Guo, YQ Shi, W Yang, YC Li, ZY Hu, YX Liu
Keywords:sertoli cells, testosterone, forskolin, spermatogenesis, plasminogen activator, blood testis barrier, testis, signal transduction, testes, expression, dependent manner, tissue type, secretion, degradation
Source:Pubmed
Affiliates:State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100080, China,
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Genistein affects HER2 protein concentration, activation, and promoter regulation in BT-474 human breast cancer cells. |
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Friday, 09 November 2007 |
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The HER2 proto-oncogene, a member of the epidermal growth factor receptor family, is overexpressed in 20-30% of breast cancers. Genistein, the main soy isoflavone, interacts with estrogen receptors (ER) and it is also a potent tyrosine kinase inhibitor. Previously, our laboratory found that genistein delayed mammary tumor onset in transgenic mice that overexpress HER2 gene. Our goal was to define the mechanism through which genistein affects mammary tumorigenesis in HER2 overexpressing mice. We hypothesized that genistein inhibits HER2 activation and expression through ER-dependent and ER-independent mechanisms. Genistein inhibited total HER2 protein expression and tyrosine phosphorylation in BT-474, an ERalpha (-) and ERbeta (+) human breast cancer cell line, however, E2 had no effect. Taken together, these data suggest that genistein has an ER-independent inhibitory effect, presumably, through tyrosine kinase inhibition activity. Genistein at 1.0 muM mimicked E2 and down-regulated HER2 protein phosphorylation when BT-474 was co-transfected with ERalpha, but not ERbeta. Although E2 and overexpression of HER2 can promote mammary tumorigenesis, an inverse relationship between ER expression and HER2 overexpression has been found in human breast cancer. We cloned a 500-bp promoter region upstream of the HER2 transcription initiation site. Co-transfection with ERalpha, but not with ERbeta, down-regulated HER2 promoter reporter in BT-474. At concentrations >/=1 muM, genistein inhibited HER2 promoter reporter in the absence of ERalpha. In conclusion, genistein at >/=1 muM inhibited HER2 protein expression, phosphorylation, and promoter activity through an ER-independent mechanism. In the presence of ERalpha, genistein mimicked E2 and inhibited HER2 protein phosphorylation. These data support genistein's chemo-prevention and potential chemo-therapeutic roles in breast cancer.
Authors:MS Sakla, NS Shenouda, PJ Ansell, RS Macdonald, DB Lubahn
Keywords:her2 protein, human breast cancer, her2 gene, genistein, protein phosphorylation, protein expression, mammary tumorigenesis, mimicked, tyrosine kinase, epidermal growth factor receptor, transgenic mice, epidermal growth factor, promoter, oncogene, soy isoflavone, independent mechanism, mammary tumor
Source:Pubmed
Affiliates:Genetics Area Program, University of Missouri, Columbia, MO, USA. |
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