Crosstalk between the aryl hydrocarbon and estrogen receptor signaling pathways in human breast cancer cells /
The aryl hydrocarbon and estrogen receptors (AhR and ER) are ligand-activated nuclear transcription factors. The crosstalk between AhR- and ER-mediated signaling pathways were investigated in both ER-positive and ER-negative human breast cancer cell lines. Induction of CYP IA I gene expression by...
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| Format: | Thesis Book |
| Language: | English |
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[Place of publication not identified] :
[publisher not identified] ;
1998.
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| Subjects: | |
| Online Access: | http://proxy.library.tamu.edu/login?url=http://proquest.umi.com/pqdweb?did=737708021&sid=1&Fmt=2&clientId=2945&RQT=309&VName=PQD |
| Summary: | The aryl hydrocarbon and estrogen receptors (AhR and ER) are ligand-activated nuclear transcription factors. The crosstalk between AhR- and ER-mediated signaling pathways were investigated in both ER-positive and ER-negative human breast cancer cell lines. Induction of CYP IA I gene expression by TCDD is regulated by the AhR complex, and Ah- responsiveness in human breast cancer cells has been correlated with ER expression. TCDD did not induce CYPIAI in ER-negative Hs578T and MCF-7/Adr' human breast cancer cells, and the relationship between expression of the ER and Ah- responsiveness was investigated in these two cell lines. Results showed that the AhR complex was expressed in both cell lines and ER or ER variants differentially modulated Ah- responsiveness in transient cotransfection studies. The data indicate that the role of ER in restoring Ah-responsiveness was highly cell-specific and dependent on expression of specific domains of the ER. MDA-MB-468 breast cancer cells were identified as the first ER-negative Ah-responsive human breast cancer cell line, and cell growth was inhibited by TCDD. Results indicated that TCDD, TGF-(X and EGF exhibit similar growth inhibitory effects, and TCDD induced transforming growth factor-alpha (TGF-(x) expression, but not epidermal growth factor (EGF) in MDA-MB-468 cells. The growth inhibitory effects of TCDD were reversed by EGFR antibody, suggesting that the mechanism of TCDD-mediated growth inhibition is due to induction of TGF-(Y., which is a potent antimitogen in MDA-MB-468 cells. Stable expression of ER in ER-negative breast cancer cells (e.g. MDA-MB-468) resulted in a less metastatic phenotype. However, E2 paradoxically inhibited cell proliferation in the ER stably-transfected cell lines and the mechanism of E2 inhibitory effects was investigated. ER stably-transfected NMA-MB-468 cells were utilized as a model for determining the role of ER in regulation of cell growth. It was shown that E2 inhibited cell growth at Go/G I phase accompanied by downregulation of cdk2- and cdk4dependent kinase activities, decreased E2F-I and PCNA proteins and induction of cdk inhibitor, p21. TCDD inhibits E2-stimulated mammary tumor growth in rodents and in MCF-7 cells; however, the E2-induced cell-cycle genes/proteins which are inhibited have not been determined. Results showed that E2 induced multiple cell cycle genes/related activities including cyclin DI, cdk7, pRb, cdk2 and cdk4 and in cotreatment studies (E2+TCDD) all of these responses were inhibited by TCDD. These results illustrate the complex crosstalk between the AhR and ER signaling pathways. |
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| Item Description: | Vita. "Major Subject: Biochemistry". |
| Physical Description: | xiii, 189 leaves : illustrations ; 28 cm. Issued also on microfiche from University Microfilms Inc. |
| Bibliography: | Includes bibliographical references: pages 150-188. |