Abstract 4174: The impact of catechol estrogen metabolism on the proliferation rate and Docetaxel (DOC) resistance in hormone-responsive cancers

Abstract

Abstract Estrogen-responsive cancers such as breast cancer (BC) and prostate cancer (PC) are on the top of the most commonly diagnosed cancers in USA. Docetaxel (DOC) is considered the first-line of therapy for both metastatic BC and castration-resistant PC. However, its use in therapeutically effective doses is associated with significant toxic reactions and tumor resistance. Estrogens (E2) play an important role in the development and progression of both malignancies. Of special importance is that the catechol E2 metabolite, 4-hydroxyestradiol (4-OHE2) enhances the proliferation of both breast and prostate normal epithelial cells. The goal of this work is to investigate the relationship between catechol-E2 metabolism and cancer cells proliferation and response to DOC. Methods: The cells were exposed to serial concentrations of E2 and 4OHE2 (0.001-10 µM) to assess their effect on cells’ growth rate over 24-92 h. Cell proliferation assays were utilized to assess the density of viable cells at different time points. Cytotoxicity assays were performed to evaluate the median inhibitory concentration (IC50) of DOC alone or in the presence of 4OHE2. Results: Exposure of the estrogen receptor (ER)-positive BC cell line MCF-7 to 0.1 µM of 17-β-hydroxyestradiol (E2) for 3 days significantly boosted the cell proliferation rate compared to control group by about 27% (P<0.05). Exposure of MCF-7 cells to the catechol estrogen metabolite 4-hydroxyestradiol (4OHE2) at 0.1µM for 3 days significally enhanced cell growth by about 31% (P<0.001). Similarly, exposure of the androgen independent, ER-positive- advanced stage PC cells PC-3 to E2 (1 µM, 3 days) significantly enhanced the growth rate by 37% (P<0.05). Moreover, our data showed that simultaneous exposure to 4OHE2 significantly antagonized the cytotoxic activity of DOC with subsequent increase in the IC50 of DOC by 18 folds (P<0.006). Conclusion: these results indicate that altered E2 metabolism with subsequent accumulation of 4-OHE2 can enhance the proliferation rate of E2-responsive cancers in addition to hindering the cytotoxic activity of DOC with subsequent reduction in DOC potency. Further research is in progress to assess the potential merit of modulating the clearance of catechol E2 as a strategy to improve the cancer response to DOC. (This project is supported by Fulbright Scholar grant FY15/16 and L’Oreal-UNESCO for Women in Science-Levant and Egypt award for MFT). Citation Format: Mai F. Tolba, Hany Omar, Ayman M. Noreddin. The impact of catechol estrogen metabolism on the proliferation rate and Docetaxel (DOC) resistance in hormone-responsive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4174. doi:10.1158/1538-7445.AM2017-4174