Tetrachlorodibenzo-p-dioxin (TCDD) may affect breast cancer by multiple mechanisms. Polycyclic aromatic hydrocarbons are metabolized by the cytochromes P450, notably P450-1A1 (CYP1A1), to reactive species contributing to breast cancer. TCDD, via the aryl hydrocarbon receptor (AhR) induces numerous genes, including CYP1A1 and P450-1B1 (CYP1B1). AhR activity, with respect to CYP1A1, depends on the estrogen receptor (ER). Preliminary data indicate that the ER is not required for basal or TCDD- induced expression of CYP1B1, suggesting that ER may not be universally required for AhR activity. TCDD also exhibits antiestrogenic activity in breast cells. The dependence of AhR activity on ER will be examined by comparing the expression and activity of TCDD-inducible genes (CYP1A1, CYP1B1) in ER- (MDA-MB-231) and ER+ (MCF7) cell lines and normal human mammary epithelia treated with/without the ER antagonist ICI 182780. MDA- MB-231 cell secrete the erbB2/3 stimulant heregulin (HRG). In ER+ cells, HRG may decrease ER, thus suppressing AhR-mediated gene induction. This hypothesis will be tested by examining expression and activity of TCDD- induced, ER-sensitive genes (e.g. CYP1A1) in the presence/absence of HRG. A timecourse of HRG's effect of CYP1A1 induction will be related to postulated loss of ER. The antiestrogenic effects of TCDD could be mediated via erbB2/3. This possibility will be examined by comparing the expression and activity of erbB2/3 in the presence/absence of TCDD.
| Angus, W G; Larsen, M C; Jefcoate, C R (1999) Expression of CYP1A1 and CYP1B1 depends on cell-specific factors in human breast cancer cell lines: role of estrogen receptor status. Carcinogenesis 20:947-55 |
