Endocrine Abstracts

Steroid sulphatase (STS) liberates sulphated oestrogens into their active forms. In the colon, evidence suggests that although initially pro-apoptotic in healthy mucosa, once malignancy occurs, oestrogens may stimulate colorectal cancer (CRC) proliferation. Moreover, greater intratumoural oestrogen synthesis is negatively associated with survival outcomes in CRC patients. However, little is known about oestrogen metabolism pathways in CRC, and whether alterations in local oestrogen synthesis and actions relate to clinical and pathological features. Furthermore, it is unknown whether manipulation of oestrogen pathways has therapeutic potential. Therefore, using qRT-PCR and immunoblotting, in healthy human colorectal tissue matched with CRC samples (n=56) we correlate the dysregulation of key oestrogen synthesis enzymes (steroid sulphatase (STS), 17β-hydroxysteroid dehydrogenase (17βHSD) type-1, type-2, type-7, and type-12) and the G-protein coupled oestrogen receptor (GPER), with patient TNM staging, lymph node infiltration, and distant metastases. In addition, ELISA assays were undertaken to ascertain the effects of oestrogens on proliferation of CRC cell lines. STS activity, 17βHSD7, and 17βHSD12 expression all showed a positive correlation with TNM staging in patient CRC samples, indicating greater oestrogen availability is linked to advanced stage disease. Increased GPER expression also significantly (P<0.05) correlated with late-stage malignancy. In CRC cell lines, over-expression of STS significantly (P<0.01) increased cell proliferation when treated with sulphated oestrogens. This effect was completely ablated when treated in combination with the STS inhibitor STX64 (P<0.001). Furthermore, we show here for the first time that the GPER agonist, G1, also stimulated CRC proliferation; with both oestrogen and G1 effects significantly inhibited with the GPER selective antagonist G15 (P<0.001). Increased STS activity and GPER expression are associated with late-stage CRC, strongly suggesting a role for oestrogens in this malignancy. Thus, reducing the availability and action of oestrogens by inhibiting STS and GPER, respectively, may have therapeutic benefits for patients with CRC.