Abstract
Endometrial cancer (EC) is associated with increased estrogen actions. Locally, estrogens can be formed from estrone-sulphate (E1-S) after cellular uptake by organic anion-transporting polypeptides (OATP) or organic anion transporters (OAT). Efflux of E1-S is enabled by ATP Binding Cassette transporters (ABC) and organic solute transporter (OST)αβ. Currently, 19 E1-S transporters are known but their roles in EC are not yet understood. Here, we analysed levels of E1-S transporters in Ishikawa (premenopausal EC), HEC-1-A (postmenopausal EC), HIEEC (control) cell lines, in EC tissue, examined metabolism of steroid precursor E1-S, studied effects of OATPs’ inhibition and gene-silencing on E1-S uptake, and assessed associations between transporters and histopathological data. Results revealed enhanced E1-S metabolism in HEC-1-A versus Ishikawa which could be explained by higher levels of OATPs in HEC-1-A versus Ishikawa, especially 6.3-fold up-regulation of OATP1B3 (SLCO1B3), as also confirmed by immunocytochemical staining and gene silencing studies, lower ABCG2 expression and higher levels of sulfatase (STS). In EC versus adjacent control tissue the highest differences were seen for ABCG2 and SLC51B (OSTβ) which were 3.0-fold and 2.1-fold down-regulated, respectively. Immunohistochemistry confirmed lower levels of these two transporters in EC versus adjacent control tissue. Further analysis of histopathological data indicated that SLCO1B3 might be important for uptake of E1-S in tumours without lymphovascular invasion where it was 15.6-fold up-regulated as compared to adjacent control tissue. Our results clearly indicate the importance of E1-S transporters in EC pathophysiology and provide a base for further studies towards development of targeted treatment.
Highlights
Endometrial cancer (EC) is the most common gynaecological malignancy [1,2,3] with the majority of EC cases diagnosed in postmenopausal women
Based on the current published data, 19 transporter proteins have a capacity for E1-S transport (Table 1), including 14 uptake transporters, eight organic anion-transporting polypeptides (OATP), five organic anion transporters (OAT), one solute anion transporter (SOAT), six efflux transporters, four ATP Binding Cassette transporters (ABC) transporters, and heterodimeric organic solute transporter (OST) αβ
When the cells were treated with E1, there was a higher formation of E2 and E1-S in Ishikawa compared to HEC-1-A cells. These results indicate that both EC cell lines markedly differ in the presence and/or actions of E1-S uptake and efflux transporters and enzymes STS and reductive HSD17B, which are responsible for the formation of E2, and sulfotransferase SULT1E1, which catalyses conjugation of estrogens
Summary
Endometrial cancer (EC) is the most common gynaecological malignancy [1,2,3] with the majority of EC cases diagnosed in postmenopausal women. In postmenopausal EC patients estrogens can be formed in peripheral sites (mainly adipose tissue) from inactive precursors including adrenal dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulphate (DHEA-S) or ovarian androstenedione or from circulating estrone-sulphate (E1-S) [13,14,15]. In peripheral sites the most potent estrogen estradiol (E2) can be formed either by the aromatase pathway from DHEA-S and DHEA via androstenedione or testosterone by the action of sulfatase (STS), 3β-hydroxysteroid dehydrogenase (HSD3B), aromatase and reductive HSD17Bs or by the STS pathway from E1-S by the action of STS and reductive HSD17Bs. Our recent data and studies of other groups revealed that in EC the sulfatase pathway has a crucial role in formation of estrogens [15,16]. Efflux transporters have important roles, as they regulate intracellular concentration of E1-S
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