Circulating estrogens in endometrial cancer cases and their relationship with tissular expression of key estrogen biosynthesis and metabolic pathways.
BACKGROUND
Endometrial cancer is the most common gynecological malignancy. Estrogen exposure is strongly associated with endometrial cancer. Whereas this cancer occurs predominantly in postmenopausal women lacking estrogen production by ovaries, the conversion of adrenal androgen-estrogen precursors to estradiol (E(2)), estrone (E(1)), and its sulfate (E(1)-S) has been well documented in peripheral tissues.


METHODS
We initially explored whether circulating levels of estrogens, measured by validated mass spectrometry assays, differ in women with endometrial cancer (n = 126) compared with healthy women (n = 110). We then evaluated by quantitative real-time PCR from purified RNA whether the expression profile of 19 estrogen-related synthesis and metabolic genes is modified in peritumoral normal endometrium (n = 36) compared with tumoral (n = 49) tissues.


RESULTS
In endometrial cancer cases, circulating levels of E(1), E(2), and E(1)-S were significantly higher compared with unaffected controls. In agreement with plasma levels, findings support an enhanced biosynthesis of E(2) in tumors. The expression of E(2) biosynthesis pathways [E(1)-S (sulfatase) --> E(1) (17beta-hydroxysteroid dehydrogenase) --> E(2)] was shown to predominate in peritumoral normal endometrium and was significantly increased in tumors. In addition, the inactivation pathways mediated by several uridine diphosphate-glucuronosyltransferases were also enhanced in endometrial tumors compared with peritumoral normal endometrium.


CONCLUSIONS
We concluded that the higher levels of circulating estrogens in women with endometrial cancer are likely associated with an imbalance of multiple biotransformation pathways in endometrial tumor tissues.
Lépine
Johanie
J
Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Canada G1V 4G2.
Audet-Walsh
Etienne
E
Grégoire
Jean
J
Têtu
Bernard
B
Plante
Marie
M
Ménard
Vincent
V
Ayotte
Pierre
P
Brisson
Jacques
J
Caron
Patrick
P
Villeneuve
Lyne
L
Bélanger
Alain
A
Guillemette
Chantal
C
D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000368:Aged; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D003851:Deoxyribonucleases / Q000737:chemistry; D016889:Endometrial Neoplasms / Q000097:blood* / Q000201:enzymology; D004717:Endometrium / Q000378:metabolism; D004798:Enzymes / Q000096:biosynthesis / Q000378:metabolism; D004967:Estrogens / Q000096:biosynthesis* / Q000097:blood*; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D012739:Gonadal Steroid Hormones / Q000097:blood; D006801:Humans; D008875:Middle Aged; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013429:Sulfatases / Q000378:metabolism
D018076:DNA, Complementary; D004798:Enzymes; D004967:Estrogens; D012739:Gonadal Steroid Hormones; D012313:RNA; D015067:17-Hydroxysteroid Dehydrogenases; D014453:Glucuronosyltransferase; D003851:Deoxyribonucleases; D013429:Sulfatases