Estrogen inhibits cell proliferation through in situ production in human thymoma.
OBJECTIVE
We showed previously estrogen receptor (ER) alpha as an independent prognostic marker in human thymoma. Estrogen sulfotransferase (EST), steroid sulfatase (STS), 17beta-hydroxysteroid dehydrogenase (17beta-HSD), and aromatase are considered to play important roles in hormone metabolism of estrogen-dependent tumors.


METHODS
We examined estrogen production using primary cultures of human thymoma epithelial cells (TEC), intratumoral estradiol (E(2)) concentrations, and status of these enzymes above using immunohistochemistry or semiquantitative reverse transcription-PCR. We then correlated these findings with clinicopathologic variables and/or clinical outcome in 132 patients.


RESULTS
E(2) inhibited cell proliferation via ERalpha in TEC, which synthesized estrone and E(2). Intratumoral E(2) concentrations were inversely correlated with EST, positively correlated with STS or 17beta-HSD type 1, and significantly higher in lower-grade or early-stage thymoma. EST status was positively correlated with tumor size, clinical stage, histologic differentiation, and Ki-67 labeling index and significantly associated with adverse clinical outcome and turned out to be a potent independent prognostic factor. STS and/or 17beta-HSD type 1 status was inversely correlated with Ki-67 labeling index and associated with lower histologic grade or early clinical stages.


CONCLUSIONS
E(2) inhibits proliferation of TEC through ERalpha, which suggests that E(2) may be effective in treatment of thymoma, especially inoperable tumor, possibly through suppressing its cell proliferation activity. EST status is a potent prognostic factor in thymoma through inactivating estrogens. In situ estrogen synthesis through intracrine mechanism therefore may play important roles in tumorigenesis and/or development of thymoma through regulation of cell proliferation in an intracrine manner.
Ishibashi
Hironori
H
Department of Pathology, Tohoku University School of Medicine, Japan. hishiba@kf6.so-net.ne.jp
Suzuki
Takashi
T
Suzuki
Satoshi
S
Moriya
Takuya
T
Kaneko
Chika
C
Nakata
Taisuke
T
Sunamori
Makoto
M
Handa
Masashi
M
Kondo
Takashi
T
Sasano
Hironobu
H
D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000096:biosynthesis; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000096:biosynthesis / Q000494:pharmacology*; D004970:Estrone / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043266:Steryl-Sulfatase / Q000235:genetics / Q000378:metabolism; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D013945:Thymoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013953:Thymus Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
D047628:Estrogen Receptor alpha; D004967:Estrogens; D012333:RNA, Messenger; D011980:Receptors, Progesterone; C097314:progesterone receptor B; D004970:Estrone; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; D001141:Aromatase; D015238:Sulfotransferases; C020122:estrone sulfotransferase; D043266:Steryl-Sulfatase