AKR1C1 and AKR1C3 may determine progesterone and estrogen ratios in endometrial cancer

• Published in: Molecular and cellular endocrinology Vol. 248; no. 1; pp. 126 - 135
• Main Authors: Rižner, Tea Lanišnik, Šmuc, Tina, Rupreht, Ruth, Šinkovec, Jasna, Penning, Trevor M.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 27.03.2006
• Subjects: 17-Hydroxysteroid Dehydrogenases - metabolism; 17β-Hydroxysteroid dehydrogenase; 20-Hydroxysteroid Dehydrogenases - genetics; 20-Hydroxysteroid Dehydrogenases - metabolism; 20α-Hydroxysteroid dehydrogenase; 3-Hydroxysteroid Dehydrogenases - genetics; 3-Hydroxysteroid Dehydrogenases - metabolism; Aldo-keto reductase; Aldo-Keto Reductase Family 1 Member C3; Animals; Endometrial Neoplasms - chemistry; Endometrial Neoplasms - genetics; Endometrial Neoplasms - metabolism; Endometrium - chemistry; Endometrium - metabolism; Estradiol - biosynthesis; Estradiol Dehydrogenases; Estrogens - analysis; Estrogens - biosynthesis; Female; Humans; Hydroxyprostaglandin Dehydrogenases - genetics; Hydroxyprostaglandin Dehydrogenases - metabolism; Isoenzymes - genetics; Isoenzymes - metabolism; Oxidoreductases - metabolism; Progesterone - analysis; Progesterone - biosynthesis; Short-chain dehydrogenase reductase; Tumor Cells, Cultured; Short-chain dehydrogenase reductase; 17β-Hydroxysteroid dehydrogenase; 20α-Hydroxysteroid dehydrogenase; Aldo-keto reductase
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2005.10.009

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), 20α-hydroxyprogesterone (20α-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 20α-hydroxysteroid dehydrogenase) in a cellular context inactivates P by forming 20α-OHP but does not catalyze the reverse reaction. We next examined the expression of AKR1C1 and AKR1C3 (type 5 17β-hydroxysteroid dehdyrogenase) 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 eleveated 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