Endocrine Abstracts (2019) 65 P138 | DOI: 10.1530/endoabs.65.P138

Targeting oestrogen synthesis and action as a novel therapy for colorectal cancer

Daljit Sidhu1, Hope Haime2, Aidan Pidd1, Angela Taylor1, Liam Cox1 & Paul Foster1

1University of Birmingham, Birmingham, UK; 2University of Birminghamsity, Birmingham, UK

Colorectal cancers (CRC) represent 9.4% of all cancers, with about 42 000 new UK cases per year. Current treatment involves surgical resection followed by radio- and chemo-therapy. 5-Fluorouracil is the standard post-operative chemotherapy although tolerance is poor due to dose-limiting toxicities and drug-resistance. New treatment strategies are therefore sorely needed. One emerging chemotherapeutic option is to target oestrogen metabolism. Our novel work reveals synthesis of biologically active oestradiol (E2) is up-regulated in CRC tissue, with this correlated with increased CRC growth. Our data suggests that 17β-hydroxysteroid dehydrogenase type-7 (HSD17B7) is the enzyme primarily responsible for the conversion of oestrone (E1) to E2 in CRC. However, little is known about the regulation of HSD17B7 and whether inhibiting its action in CRC can block E2 synthesis. Here using LC–MS/MS methods and in various CRC cell lines (HCT116, HT-29, LoVo, SW620), we investigated whether these cells can all convert E1 to E2. We have also examined if starving the cells of oestrogens and then replacing oestrogen (E1 or E2) concentrations can regulate HSD17B7 expression. We have also synthesised HSD17B7 inhibitors that have been used to block E1 to E2 conversion in CRC cell lines. CRC cell lines, apart from HT-29, synthesised E1 to E2 with a greater conversion rate when compared to E2 to E1 synthesis. This suggests that CRC favours E2 synthesis. Oestrogen starvation of the CRC cells resulted in a significant increase in HSD17B7 expression. Replacement of oestrogens did not decrease HSD17B7 expression to control levels. HSD17B7 inhibitors significantly (P<0.01) reduced E2 synthesis when CRC cells were treated with E1. These data suggest that low oestrogen concentrations can increase HSD17B7 expression and activity in CRC. Furthermore, we demonstrate that inhibition of HSD17B7 can reduce E2 synthesis in CRC and this may be a new treatment option for this malignancy.

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