Sulfatase and aromatase pathway

The intratumoral production of estradiol-17beta (E2) from circulating steroid hormone precursors plays an essential role in estrogen-related breast and epithelial ovarian cancer (EOC). There are two possible pathways producing E2, one being the sulfatase pathway starting from estrone sulfate, and one being the aromatase pathway which starts with DHEA-S. Both routes rely on two crucial enzymes: STS for estrogen activation and SULT1E1 for inactivation. Research indicates that an increased STS expression and E2 production is associated with cancer progression. However, sulfonation of E2 via SULT1E1 not only reduces proliferative effects of estrogens on hormone-sensitive tumor cells, but also generates water-soluble estrogen sulfates consequently leading to an increased excretion of sulfonated E2. This helps preventing a metabolic activation of the hormone into potentially mutagenic catechol metabolites. Thus, targeting estrogen-modifying enzymes is a potential endocrine therapy strategy for patients with estrogen-sensitive EOC. This pathway is based on Figure 1 from: Mungenast, F., Aust, S., Vergote, I., Vanderstichele, A., Sehouli, J., Braicu, E., Mahner, S., Castillo‑Tong, D. C., Zeillinger, R., Thalhammer, T."Clinical significance of the estrogen-modifying enzymes steroid sulfatase and estrogen sulfotransferase in epithelial ovarian cancer". Oncology Letters 13, no. 6 (2017): 4047-4054. https://doi.org/10.3892/ol.2017.5969

肿瘤内由循环类固醇激素前体产生的雌二醇-17β（E2）在雌激素相关的乳腺癌和上皮性卵巢癌（EOC）中发挥着至关重要的作用。E2的产生存在两种可能的途径，其一为从雌酮硫酸酯开始的硫酸酯酶途径，其二为以脱氢表雄酮硫酸酯（DHEA-S）为起点的芳香化酶途径。这两条途径均依赖于两种关键酶：STS酶负责雌激素的活化，SULT1E1酶负责其失活。研究表明，STS表达增加和E2产生与癌症进展相关。然而，E2通过SULT1E1的硫酸化不仅降低了雌激素对激素敏感肿瘤细胞的增殖作用，而且生成了水溶性雌激素硫酸酯，从而增加了硫酸化E2的排泄。这有助于防止激素代谢活化成潜在的致突变儿茶酚类代谢物。因此，针对雌激素修饰酶是雌激素敏感型EOC患者潜在内分泌治疗策略。该途径基于Mungenast等人在《Oncology Letters》杂志上发表的论文中的图1：“雌二醇修饰酶类固醇硫酸酯酶和雌激素硫酸转移酶在上皮性卵巢癌中的临床意义”。Oncology Letters 13, no. 6 (2017): 4047-4054. https://doi.org/10.3892/ol.2017.5969