Estrogen signaling ability in human endometrial cancer through the cancer-stromal interaction.
The estrogen pathway plays an important role in the etiology of human endometrial carcinoma (EC). We examined whether estrogen biosynthesis in the tumor microenvironment promotes endometrial cancer. To examine the contribution of stromal cells to estrogen signaling in EC, we used reporter cells stably transfected with the estrogen response element (ERE) fused to the destabilized green fluorescent protein (GFP) gene. In this system, the endometrial cancer stromal cells from several patients activated the ERE of cancer cells to a variable extent. The GFP expression level increased when testosterone, a substrate for aromatase, was added. The effect was variably inhibited by aromatase inhibitors (AIs), although the response to AIs varied among patients. These results suggest that GFP expression is driven by estrogen synthesized by aromatase in the endometrial cancer stromal cells. In a second experiment, we constructed an adenovirus reporter vector containing the same construct as the reporter cells described above, and visualized endogenous ERE activity in primary culture cancer cells from 15 EC specimens. The GFP expression levels varied among the cases, and in most primary tissues, ERE activities were strongly inhibited by a pure anti-estrogen, fulvestrant. Interestingly, a minority of primary tissues in endometrial cancer showed ERE activity independent of the estrogen-ER pathway. These results suggest that AI may have some therapeutic value in EC; however, the hormonal microenvironment must be assessed prior to initiating therapy.
Department of Medical Technology, Tohoku University School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 981-0872, Japan. m-matsumoto@mail.tains.tohoku.ac.jp
Mitsuyo
M
Matsumoto
Yuri
Y
Yamaguchi
Yuko
Y
Seino
Atsushi
A
Hatakeyama
Hiroyuki
H
Takei
Hitoshi
H
Niikura
Kiyoshi
K
Ito
Takashi
T
Suzuki
Hironobu
H
Sasano
Nobuo
N
Yaegashi
Shin-Ichi
S
Hayashi
D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000494:pharmacology; D001943:Breast Neoplasms; D002450:Cell Communication / Q000502:physiology; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology*; D004967:Estrogens / Q000096:biosynthesis / Q000378:metabolism*; D005260:Female; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*; D013739:Testosterone / Q000494:pharmacology
D047072:Aromatase Inhibitors; D004967:Estrogens; D011960:Receptors, Estrogen; D049452:Green Fluorescent Proteins; D013739:Testosterone; D015067:17-Hydroxysteroid Dehydrogenases; D001141:Aromatase