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790 In RL95–2 and KLE model cell lines of moderately and poorly differentiated endometrial carcinoma, estrogens can be formed via the sulfatase pathway
  1. R Pavlič1,
  2. K Marton1,
  3. M Gjorgoska1,
  4. M Sinreih1,
  5. E Hafner1,
  6. S Poschner2,
  7. W Jäger2 and
  8. TL Rižner1
  1. 1University of Ljubljana, Faculty of Medicine, Institute of Biochemistry and Molecular Genetics, Ljubljana, Slovenia
  2. 2University of Vienna, Department of Pharmaceutical Chemistry, Vienna, Austria


Introduction/Background*Endometrial cancer (EC) is the most common gynecological malignancy in the western world. EC has traditionally been divided into type I, which is estrogen dependent, and type II, where associations with estrogens were only recently uncovered. Both types of EC arise after menopause when tumor tissue depends on formation of estrogens from inactive steroid precursors. In EC, active estrogens can be formed from circulating estrone sulfate (E1-S) via sulfatase pathway by the sulfatase (STS) and reductive 17β-hydroxysteroid dehydrogenase type 1 (HSD17B1) enzymes.

Methodology In our study, we aimed to investigate the role of estrogens in model cell lines of moderately (type I) and poorly (type II) differentiated EC: RL95-2 and KLE cells, respectively. We evaluated expression of genes involved in E1-S transport, estrogen biosynthesis and oxidative metabolism, and examined cellular uptake of E1-S, formation of estrogens from E1-S, and effects of estrogens on cell proliferation.

Result(s)*Gene expression analysis revealed up-regulated expression of several E1-S uptake transporters: SLCO1A2 (3434-fold), SLCO1B3 (2302-fold), SLCO1C1 (381-fold), SLCO3A1 (19-fold), SLC22A9 (5-fold), SLC10A6 (5-fold), and functional studies showed increased E1-S uptake in KLE cells versus RL95-2 cells. Higher levels of STS were confirmed in RL95-2 cells, which also better metabolized E1-S to estrone (E1), compared to KLE cells. In KLE cells, disturbed balance in the expression of genes encoding reductive and oxidative HSD17B enzymes enhanced activation of E1 to estradiol (E2), compared to RL95-2 cells, and physiological E1 concentrations stimulated KLE cell proliferation. Additionally, gene expression analysis in KLE versus RL95-2 cells indicated increased CYP1B1 expression (17-fold) as responsible for formation of carcinogenic 4-hydroxycatechols, and down-regulation of genes that encode phase II metabolic enzymes: COMT (6-fold), NQO1 (13-fold), NQO2 (7-fold), and GSTP1 (2-fold). This suggested decreased detoxification of carcinogenic metabolites in KLE cells.

Conclusion*Our results indicate that in cell lines of type I and type II EC, estrogens can be formed via the sulfatase pathway, and can promote proliferation of poorly differentiated EC. This supports the importance of estrogens in poorly differentiated (type II) EC. Further studies in tissue samples of type II EC are needed to confirm our findings.

Funding Slovenian Research Agency, grant J3-8212 to T.L.R., Young Researcher grant to R.P.; Austrian Science Fund (FWF), grant I 3417-B31 to W.J.

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