Aryl hydrocarbon receptor-mediated antiestrogenic activity in human breast cancer cells /
It has been hypothesized that exposure to endocrine disruptors such as environmental estrogens may cause various reproductive and developmental abnormalities in humans and wildlife. In particular, organochlorine environmental contaminants such as PCBS and pesticides have been characterized as enviro...
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| Format: | Thesis Book |
| Language: | English |
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[Place of publication not identified] :
[publisher not identified] ;
1999.
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| Subjects: | |
| Online Access: | http://proxy.library.tamu.edu/login?url=http://proquest.umi.com/pqdweb?did=731686631&sid=1&Fmt=2&clientId=2945&RQT=309&VName=PQD |
| Summary: | It has been hypothesized that exposure to endocrine disruptors such as environmental estrogens may cause various reproductive and developmental abnormalities in humans and wildlife. In particular, organochlorine environmental contaminants such as PCBS and pesticides have been characterized as environmental estrogens. Results of the present studies show that several organochlorine compounds including PCBs, hydroxy-PCBs and phenolics as well as naturally-occurring flavonoids have minimal estrogenic activity and some have significant antiestrogenic activity in in vitro assays in breast cancer cells. Additionally, previously reported synergistic interactions between organochlorine pesticides were not observed in multiple in vivo and in vitro assays. Indole-3-carbinol (I3C) is a major component of Brassica vegetables and diindolylmethane (DIM) is the major acid-catalyzed condensation product derived from l3C. Both compounds competitively bind to the aryl hydrocarbon receptor (AhR) with relatively low affinity and did not significantly induce CYP1A1-dependent ethoxyresorufin O-deethylase (EROD) activity, CYP1A1 mRNA levels or reporter gene activity in T47D human breast cancer cells. However, I3C or DIM partially inhibited several 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced responses and bole compounds were characterized as partial AhR antagonists. DIM inhibits E2-induced proliferation of MCF-7 cells, downregulates nuclear ER protein levels and inhibits hormone-induced transactivation of E2- responsive genes. Comparable in vitro antiestrogenic responses were observed for TCDD and DIM in this study and these data confirm that both compounds elicit AhR-mediated antiestrogenic responses. However, the antitumorigenic effects of DIM are not accompanied by apparent toxic effects or induction of hepatic CYP1A1-dependent activity suggesting that DIM represents a new class of non-toxic AhR-based antiestrogens for treatment of breast cancer. The antiestrogenic activity of TCDD and DIM is mediated through crosstalk between the AhR and ER signaling pathways. Suppression subtractive hybridization was utilized to identify E2-induced genes downregulated by TCDD and DIM. The results indicate that 43 of the clones identified in this study have sequence homology to previously described genes; in addition, three potential novel sequences were also identified. Expression patterns of these genes were confirmed by dot blot, Northern blot, and DNA microarray analyses. Results of this study provide more information on E2-regulated genes that are targeted by AhR agonists. |
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| Item Description: | Vita. "Major Subject: Toxicology". |
| Physical Description: | xii, 198 leaves : illustrations ; 28 cm. Issued also on microfiche from University Microfilm Inc. |
| Bibliography: | Includes bibliographical references (leaves 161-197). |