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Department of Obstetrics and Gynaecology, British Columbia Women’s Hospital, University of British Columbia, Vancouver, British Columbia, V6H 3V5, Canada
Address all correspondence and requests for reprints to: Peter C. K. Leung, Ph.D., Department of Obstetrics and Gynaecology, University of British Columbia, 2H30-4490 Oak Street, British Columbia Women’s Hospital, Vancouver, British Columbia, Canada, V6H 3V5. E-mail: peleung{at}interchange.ubc.ca
Most epithelial ovarian tumors appear to arise from the ovarian
surface epithelium (OSE). Even though it has been suggested that
estrogen may be associated with ovarian tumorigenesis, the exact role
of estrogen in the regulation of apoptosis in neoplastic OSE cells
remains uncertain. Immortalized OSE (IOSE) cell lines were generated
from human normal OSE. These cell lines represent early neoplastic
(IOSE-29), tumorigenic (IOSE-29EC), and late neoplastic (IOSE-29EC/T4
and IOSE-29EC/T5) transformation stages from human normal OSE. The
present studies demonstrated that both mRNAs and proteins of
estrogen receptor (ER) 
and ß were expressed in IOSE cell lines.
No difference was observed in normal OSE and IOSE-29 cells, whereas
treatment with 17ß-estradiol (E2;
10-8–10-6
M) resulted in an increased thymidine incorporation and DNA
content per culture in IOSE-29EC cells. This effect of E2
was attenuated with tamoxifen treatment (10-6
M), the estrogen antagonist, suggesting that the effect of
E2 is mediated through specific ERs. There was no
stimulatory effect on thymidine incorporation before day 6, but after 6
days of E2 treatment, thymidine incorporation was
significantly increased. Because the ratio of thymidine
incorporation to DNA content per culture did not change, this
E2 effect does not appear to indicate stimulation of
proliferation but, rather, inhibition of apoptosis. In addition,
treatment with tamoxifen (10-6
M) induced apoptosis up to 3-fold in IOSE-29EC cells,
whereas cotreatment with E2
(10-8–10-6
M) plus tamoxifen attenuated tamoxifen-induced apoptosis in
a dose-dependent manner. Both proapoptotic bax and antiapoptotic bcl-2
at messenger RNA (mRNA) and protein levels were expressed in IOSE cell
lines. Interestingly, treatments with E2 resulted in a
significant increase of bcl-2 mRNA and protein levels (2- and
1.7-fold, respectively), whereas no difference was observed in bax
mRNA level. Thus, E2 may enhance survival of IOSE-29EC by
up-regulating bcl-2, and antiapoptotic bcl-2 may be a dominant
regulator of apoptotic pathway in these cells. In conclusion, the
present study indicates that early neoplastic (IOSE-29), tumorigenic
(IOSE-29EC), and late neoplastic (IOSE-29EC/T4 and T5) OSE cells
expressed both ER and ERß at the mRNA and protein levels. In
addition, E2 prevented tamoxifen induced-apoptosis through
ERs. The mechanism of E2 action may be associated with
up-regulation of bcl-2 gene at mRNA and protein levels.
These results suggest that estrogen may play a role in ovarian
tumorigenesis by preventing apoptosis in tumorigenic OSE cells.
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