The Sulfatase Pathway for Estrogen Formation: Targets for the Treatment and Diagnosis of Hormone-Associated Tumors

Abstract

The extragonadal synthesis of biological active steroid hormones from their inactive precursors in target tissues is named “intracrinology.” Of particular importance for the progression of estrogen-dependent cancers is the in situ formation of the biological most active estrogen, 17beta-estradiol (E2). In cancer cells, conversion of inactive steroid hormone precursors to E2 is accomplished from inactive, sulfated estrogens in the “sulfatase pathway” and from androgens in the “aromatase pathway.” Here, we provide an overview about expression and function of enzymes of the “sulfatase pathway,” particularly steroid sulfatase (STS) that activates estrogens and estrogen sulfotransferase (SULT1E1) that converts active estrone (E1) and other estrogens to their inactive sulfates. High expression of STS and low expression of SULT1E1 will increase levels of active estrogens in malignant tumor cells leading to the stimulation of cell proliferation and cancer progression. Therefore, blocking the “sulfatase pathway” by STS inhibitors may offer an attractive strategy to reduce levels of active estrogens. STS inhibitors either applied in combination with aromatase inhibitors or as novel, dual aromatase-steroid sulfatase inhibiting drugs are currently under investigation. Furthermore, STS inhibitors are also suitable as enzyme–based cancer imaging agents applied in the biomedical imaging technique positron emission tomography (PET) for cancer diagnosis.

Antiestrogenic Activity and Possible Mode of Action of Certain New Nonsteroidal Coumarin-4-acetamides

“…This compound has a number of advantages over all other antiestrogens and should be investigated for the treatment of ER-positive breast cancer and other estrogen-sensitive malignancies [20,21]. In addition, aromatase enzyme is involved in the last step of the estrogen biosynthetic pathway [27]. A number of coumarin derivatives bearing an imidazole ring at position four have been designed and synthesized as strong and selective aromatase inhibitors (AIs) [28].…”

Fate and transport of free and conjugated estrogens during soil passage

“…In the human body, the level of biologically-active estrogens is of particular interest as they are responsible for the progression of estrogen-dependent cancers (Secky et al, 2013). In the literature, two potential pathways for the sulfate conjugation of E1 are described: a) the sulfatase pathway, which converts the inactive estrogen to the active estrogen, and b) the sulfotransferase pathway, which converts the active estrogen to the inactive form (Secky et al, 2013).…”

“…In the literature, two potential pathways for the sulfate conjugation of E1 are described: a) the sulfatase pathway, which converts the inactive estrogen to the active estrogen, and b) the sulfotransferase pathway, which converts the active estrogen to the inactive form (Secky et al, 2013). Both pathways are triggered by enzymes, and the correct function of their interplay is of great importance for human health and well-known in medical sciences, albeit the sulfate conjugation or de-conjugation is only one of several physiological transformation pathways.…”

“…E1-3S to E1), whereas arylsulfotransferase converts the active to the inactive estrogen (e.g. E1 to E1-3S) (Secky et al, 2013). While the detection of arylsulfatase is described in soil (e.g.…”

“…Proposed enzymatic transformation pathways for E1 and E1-3S via the enzymes arylsulfatase (ASTS) and arylsulfotransferase (ASULT), modified afterSecky et al (2013).…”