Crosstalk between the aryl hydrocarbon and estrogen receptor signaling pathways in human breast cancer cells.
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文摘
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 CYP1A1 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 CYP1A1 in ER-negative Hs578T and MCF-7/Adr$\rm\sp{R}$ 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-$\alpha$ and EGF exhibit similar growth inhibitory effects, and TCDD induced transforming growth factor-alpha (TGF-$\alpha)$ 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-$\alpha,$ 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 MDA-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/G1 phase accompanied by downregulation of cdk2- and cdk4-dependent kinase activities, decreased E2F-1 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 D1, 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.