The Significance of the Sulfatase Pathway for Local Estrogen Formation in Endometrial Cancer

Abstract

Endometrial cancer (EC) is the most common estrogen-dependent gynecological malignancy in the developed World. To investigate the local formation of estradiol (E2), we first measured the concentrations of the steroid precursor androstenedione (A-dione) and the most potent estrogen, E2, and we evaluated the metabolism of A-dione, estrone-sulfate (E1-S), and estrone (E1) in cancerous and adjacent control endometrium. Furthermore, we studied expression of the key genes for estradiol formation via the aromatase and sulfatase pathways. A-dione and E2 were detected in cancerous and adjacent control endometrium. In cancerous endometrium, A-dione was metabolized to testosterone, and no E2 was formed. Both, E1-S and E1 were metabolized to E2, with increased levels of E2 seen in cancerous tissue. There was no significant difference in expression of the key genes of the aromatase (CYP19A1) and the sulfatase (STS, HSD17B1, HSD17B2) pathways in cancerous endometrium compared to adjacent control tissue. The mRNA levels of CYP19A1 and HSD17B1 were low, and HSD17B14, which promotes inactivation of E2, was significantly down-regulated in cancerous endometrium, especially in patients with lymphovascular invasion. At the protein level, there were no differences in the levels of STS and HSD17B2 between cancerous and adjacent control tissue by Western blotting, and immunohistochemistry revealed intense staining for STS and HSD17B2, and weak staining for SULT1E1 and HSD17B1 in cancerous tissue. Our data demonstrate that in cancerous endometrium, E2 is formed from E1-S via the sulfatase pathway, and not from A-dione via the aromatase pathway.

Identification of metabolomic biomarkers for endometrial cancer and its recurrence after surgery in postmenopausal women

“…These have been associated with EC and breast cancer progression, supporting the role of bradykinin in tumors originating from steroid sensitive tissues (39,40). Sulfated androgens were also higher in type I EC cases, consistent with the reported implication of sulfated steroids in this histotype (8,(41)(42)(43)(44). Furthermore, our data identified heme as a putative biomarker of type II EC and highlighted modifications in pathways closely related to heme synthesis, namely the tetrahydrofolate-serine/glycine pathway (45).…”

Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders

“…Additionally, STS can metabolise E1S and E2S sulphate to bioactive E1 and E2 respectively. STS is expressed in normal endometrial tissues and in endometrial cancers [49,50]. STS expression and activity is increased during decidualisation of endometrial stromal cells in vitro consistent with a detectable increase in oestrogens detected in tissue samples recovered during the secretory phase [3,46].…”

Estradiol metabolites as biomarkers of endometrial cancer prognosis after surgery

“…Obesity is a known risk factor of EC [4] and this may be partly related to the fact that adipose tissue represents a major source of estrogen synthesis in postmenopausal women, actively converting adrenal and androgen precursors to estrogens resulting in increased serum bioavailable estradiol (E 2 ) [5,6]. Previous work by our group and others has revealed that the potent estrogen E 2 primarily derive from conversion of estrone-sulfate (E 1 -S) in EC tumors rather than aromatization of androgens by the aromatase (CYP19), which has barely detectable expression levels in EC cells [7][8][9][10]. Besides, E 2 and E 1 may be converted into numerous biologically active derivatives with varying mitogenic and genotoxic properties by the action of various cytochrome P450 and catechol-O-methyl transferase enzymes [11].…”