Endocrine Abstracts

Oestrogens impact colorectal cancer (CRC) development and proliferation. Biologically active oestrogens, oestrone (E₁) and oestradiol (E₂), are metabolised through hydrolysis of their sulfated forms (oestrone sulfate (E₁S) and oestradiol sulfate) by steroid sulfatase (STS). We have shown that increased STS activity drives CRC proliferation via oestrogen hydrolysis. We have also identified that CRC expresses the necessary organic anion transporter polypeptides (OATPs) for sulfated oestrogen uptake. However, what regulates STS activity and OATPs expression in CRC is poorly understood. In breast and prostate cancer inflammatory mediators, such as TNFα, increase STS activity. Therefore, we hypothesised that inflammatory mediators regulate STS activity and OATPs expression in CRC. To test this, we calculated correlation coefficients between inflammatory mediators (TNFα, IL6, IL8) and STS and OATP expression in human colon adenocarcinoma (COAD) RNA-Seq data (n=440) from The Cancer Genome Atlas (TCGA). We also tested how inflammation effects STS activity, OATP expression, and E₁S uptake in CRC cells. Analysis of COAD data demonstrated a positive correlation between TNFα and OATP2B1 expression (r=0.32, P<0.0001) suggesting TNFα upregulates OATP2B1 in CRC. No correlations were observed between other inflammatory mediators and OATP expression. When examined in vitro, TNFα significantly upregulated OATP2B1 mRNA and protein expression in HCT116 cells, and E₁S uptake was also significantly increased from 26.78 pmol/mg to 35.01 pmol/mg. While IL6 and IL8 had no effect on STS activity, 20 ng/ml and 40 ng/ml TNFα significantly increased STS activity from 7.02 pmol/mg/h to 40.21 pmol/mg/h (P<0.05) and 57.24 pmol/mg/h (P<0.001) respectively in HCT116 cells. These novel findings show that in CRC TNFα increases both the uptake of E₁S via OATP2B1 and its subsequent hydrolysis by STS. Coupled with our previous findings where increased STS activity results in greater CRC proliferation, this data suggests TNFα is an important regulator of oestrogen uptake and metabolism.