Endocrine Abstracts

Colorectal cancer (CRC) is the third most common cancer worldwide with incidence expected to rise. Although not traditionally viewed as a hormonal cancer, evidence suggests peripheral synthesis of active oestrogens worsens prognosis. Oestrogen metabolising enzymes include steroid sulphatase (STS), which desulphates oestrogens into their active forms, and 17β-hydroxysteroid dehydrogenases (17βHSD), which are estrogen oxidoreductase enzymes. We have previously shown STS activity is increased in human CRC compared to matched-normal tissue. However, the impact of this increased oestrogen de-sulphation on CRC proliferation is unknown. Furthermore, the expression and activity of 17βHSD-1, 17βHSD-7 and 17βHSD-12, all of which reduce the less active oestrone (E₁) to the more potent oestradiol (E₂), have not been fully examined in CRC. Thus, this project investigated the proliferative effects of E₁ and E₂ treatment and overexpression of STS in CRC cell lines. Additionally, how these cell lines metabolised oestrogen was analysed using a novel uPLC-MS/MS technique. Protein and mRNA expression of 17βHSDs capable of reducing E₁–E₂ were examined in human CRC tissue and cell lines. Oestrogen (E₁ and E₂) and STS overexpression increased proliferation of the CRC cell line HCT116. Proliferation also increased in response to G1, a G-protein-coupled estrogen receptor 1 (GPER) agonist. LC-MS/MS indicated HCT116 cells reduced E₁–E₂ most likely catalysed by 17βHSD-12. In human CRC 17βHSD-1 was not expressed, however 17βHSD-7 and -12 expression was significantly elevated (P<0.0005) compared to matched normal tissue. GPER was also found to be expressed in the colon. Together these findings suggest the majority of human CRC escalate intratumoural E₂ concentrations through STS and 17βHSD-12. This local oestrogen rise likely acts through GPER to augment tumour proliferation. Therefore, STS, 17BHSD-12 and GPER inhibitors may benefit many CRC patients.

Disclosure: Medical Research Council UK PhD Studentship. Society for Endocrinology Early Career Award.