Estrogen Receptor Signaling and Crosstalk with the Ah Receptor in Endometrial Cancer Cells

Abstract

Common risk factors for the development of endometrial and breast cancer include early menarche, late menopause, null parity, and later age at first birth, indicating that “lifetime” exposure to estrogens increases the incidence of both tumors. In contrast, smoking protects against the development of endometrial cancer, whereas the role of smoking in breast cancer incidence is equivocal and may be dependent on the timing and duration of smoking. Constituents of cigarette smoke bind and activate the aryl hydrocarbon receptor (AhR), and research in this laboratory has focused on characterizing the inhibitory AhR-estrogen receptor (ER) a crosstalk in endometrial and breast cancer cell lines. Both Ishikawa and ECC1 endometrial cancer cells express the AhR and ERoc proteins by Western blot analysis. Moreover, AhR ligands such as benzo[a]pyrene (BaP) and/or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induce CYP1A1-dependent activity or reporter gene activity in cells transfected with constructs containing dioxin-responsive elements as promoters. Estrogen responsiveness was also confirmed in these cells, as evidenced by gene/reporter gene assay and the induction of cell proliferation by 17β-estradiol (E2). Inhibitory AhR-ERα crosstalk studies have shown that TCDD and/or BaP inhibit E2-induced growth of endometrial cancer cells and also block hormone-activated reporter gene/gene responses. Although there are several possible mechanisms for the interaction between AhR and ERα signaling pathways, the role of AhR-mediated downregulation of ERα will be discussed as one possible mechanism. In addition, selective AhR modulators have been developed for the treatment of breast and endometrial cancer and the potential use of these compounds alone or in combination with tamoxifen will be outlined.