AKR1C1 and AKR1C3 may determine progesterone and estrogen ratios in endometrial cancer.
Endometrial cancer is the most common malignancy of the female genital tract. Its incidence correlates with prolonged estrogen stimulation unopposed by progesterone or synthetic progestins. Estrogen and progestin action is regulated at the pre-receptor level, by interconversion of active hormones (estradiol (E2), progesterone (P)) with their inactive counterparts (estrone (E1), 20alpha-hydroxyprogesterone (20alpha-OHP)) in target tissues. Expression of enzymes that control the ratio of E2 and P may thus play role in the disease process. We first confirmed that AKR1C1 (human 20alpha-hydroxysteroid dehydrogenase) in a cellular context inactivates P by forming 20alpha-OHP but does not catalyze the reverse reaction. We next examined the expression of AKR1C1 and AKR1C3 (type 5 17beta-hydroxysteroid dehydrogenase) in 16 paired specimens of endometrial cancer and adjacent normal endometrium. Quantification by isoform specific real-time PCR revealed higher expression of AKR1C1 in nine specimens and higher expression of AKR1C3 in four specimens of endometrial cancer. Importantly, upregulation of both enzymes in the same specimen was observed. Since AKR1C1 inactivates P its elevated expression in diseased endometrium may contribute to diminished protection by P, while elevated expression of AKR1C3 which forms E2 in vivo, may contribute to the enhanced estrogen action. It is suggested that the expression of AKR1C1 and AKR1C3 in endometrial cancer will govern the ratio of P:E2.
Rizner
Tea Lanisnik
TL
Institute of Biochemistry, Medical Faculty, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia. Tea.Lanisnik-Rizner@mf.uni-lj.si
Smuc
Tina
T
Rupreht
Ruth
R
Sinkovec
Jasna
J
Penning
Trevor M
TM
D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D015089:20-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000818:Animals; D016889:Endometrial Neoplasms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004717:Endometrium / Q000737:chemistry / Q000378:metabolism; D004958:Estradiol / Q000096:biosynthesis; D004960:Estradiol Dehydrogenases; D004967:Estrogens / Q000032:analysis / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D011374:Progesterone / Q000032:analysis / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
D004967:Estrogens; D007527:Isoenzymes; D011374:Progesterone; D004958:Estradiol; D010088:Oxidoreductases; D015067:17-Hydroxysteroid Dehydrogenases; D015096:3-Hydroxysteroid Dehydrogenases; D015089:20-Hydroxysteroid Dehydrogenases; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D004960:Estradiol Dehydrogenases; C523763:HSD17B2 protein, human