Clinical significance of the estrogen-modifying enzymes steroid sulfatase and estrogen sulfotransferase in epithelial ovarian cancer

摘要

17β-estradiol (E2) can contribute to the progression of epithelial ovarian cancer (EOC). Although the majority of patients with EOC are postmenopausal woman, when de novo estrogen production in the ovary has ceased, ovarian cancer cells remain exposed to estrogens synthesized locally in the cancer cells from inactive sulfonated steroid hormone precursors-such as estrone sulfate taken up from the circulation via the sulfatase pathway. An abundance of the estrogen-modifying enzymes, including estrogen-activating steroid sulfatase (STS) and estrogen-inactivating estrogen-sulfotransferase (SULT1E1), is important for providing active estrogen to EOC cells. Therefore, the present study determined the levels of SULT1E1, STS and estrogen receptor α (ERα) protein in paraffin-embedded specimens from 206 patients with Federation of Gynecology and Obstetrics stage II–IV EOC treated with debulking surgery and standard platinum-based adjuvant chemotherapy. The levels of STS, SULT1E1 and ERα were assessed by automated quantitative microscopy-based image analysis subsequent to immunohistochemical staining. Significantly higher SULT1E1 levels were observed in better differentiated EOC tumors compared to grade 3 EOC tumors (P=0.001). STS and SULT1E1 levels were positively associated with ERα abundance (P<0.001 and P=0.001, respectively). In advanced stage high-grade serous EOC (HGSOC; n=132), the most frequent and lethal type of ovarian cancer, SULT1E1 expression was significantly associated with a better overall survival rate (hazard ratio 0.66, 95% confidence interval, 0.45–0.94; P=0.005). These results highlight the importance of SULT1E1-mediated estrogen inactivation in EOC, particularly HGSOC. Therefore, targeting the sulfatase pathway is a potential endocrine therapeutic intervention for certain patients with estrogen-responsive EOC.