Transdominant suppression of estrogen receptor signaling by progesterone receptor ligands in uterine leiomyoma cells.
Uterine leiomyomas develop in reproductive-age women with high frequency and are dependent on the production of ovarian hormones. While it is generally accepted that these tumors are estrogen (E(2))-responsive, the role of progesterone (P(4)) in modulating tumor growth is less clear. In the present study, an in vivo/in vitro rat model was used to characterize progesterone receptor (PR) isoform expression in uterine leiomyoma and investigate PR signaling using progestins and antiprogestins in the leiomyoma-derived cell line ELT-3. PR-A was the predominant isoform expressed in normal myometrium, leiomyomas and ELT3 cells. In the normal myometrium, PR-A and PR-B levels varied during the estrous cycle with low ratios of PR-A relative to PR-B (PR-A/PR-B) coinciding with times of cell proliferation. Although PR ligands had no effect on basal levels of uterine leiomyoma cell proliferation in vitro, both progestins and antiprogestins inhibited E(2)-stimulated cell proliferation. In addition, E(2)-stimulated transactivation of an estrogen-response-element reporter gene as well as E(2)-induced upregulation of the PR were also inhibited by PR ligands. These data indicate that PR ligands can transdominantly suppress estrogen receptor signaling and stimulation of uterine leiomyoma cell growth.
Hodges
Leslie C
LC
Department of Carcinogenesis, University of Texas MD Anderson Cancer Center, Science Park-Research Division, PO Box 389, Smithville, TX 78957, USA.
Houston
Kevin D
KD
Hunter
Deborah S
DS
Fuchs-Young
Robin
R
Zhang
Zhiming
Z
Wineker
Richard C
RC
Walker
Cheryl L
CL
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D030762:Estrous Cycle / Q000378:metabolism; D005260:Female; D007889:Leiomyoma / Q000473:pathology*; D008024:Ligands; D009215:Myometrium / Q000166:cytology; D011372:Progestins / Q000494:pharmacology; D051381:Rats; D011960:Receptors, Estrogen / Q000502:physiology*; D011980:Receptors, Progesterone / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000473:pathology*
D008024:Ligands; D011372:Progestins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; D004958:Estradiol