Catechol estrogens induce proliferation and malignant transformation in prostate epithelial cells

In the current study, the non-transformed prostatic epithelial cells (BPH-1) were exposed to the catechol estrogens (CE) 2-hydroxyestradiol (2-OHE2) or 4-hydroxyestradiol (4-OHE2), or the parent hormone 17-β-estradiol (E2) at an equimolar concentration (1μM) for a period of 6 weeks. It was found that both 2-OHE2 and 4-OHE2 have more potent proliferation-enhancing effect than E2. Exposure to 2-OHE2, 4-OHE2 or E2 resulted in a significant increase in the protein abundance of cyclin D1 and c-myc. The treated cells exhibited a shift toward the proliferative phase as indicated by FACScan. BPH-1 cells treated with 4-OHE2 showed increased abundance of estrogen receptor-α (ERα) and its downstream IGF-1R. Reduced abundance of estrogen receptor-β (ERβ) and its downstream tumor suppressor FOXO-1 were observed in cells exposed to E2, 2-OHE2 and, to a greater extent, 4-OHE2. Comet assay revealed that CE, especially 4-OHE2, elicited significant genotoxic effects as compared to E2. 4-OHE2 showed greater ability to neoplastically transform BPH-1 cells as indicated by increased colony forming capacity in soft agar and matrix invasion. In conclusion, in vitro exposure to CE could neoplastically transform human prostatic epithelial cells. Further, 4-OHE2 is more carcinogenic to prostate epithelial cells than the parent hormone E2.