Reproductive Sciences, Vol. 12, No. 4, 285-292 (2005)
DOI: 10.1016/j.jsgi.2005.01.003
© 2005 SAGE Publications
Progesterone-Induced Inhibition of Growth and Differential Regulation of Gene Expression in PRA- and/or PRB-Expressing Endometrial Cancer Cell Lines
Ellen Smid-Koopman, MD, PhD
Liesbeth C. M. Kuhne
Eline E. Hanekamp, PhD
Susanne C.J.P. Gielen, MD
Petra E. De Ruiter, BSc
J. Anton Grootegoed, PhD
Theo J.M. Helmerhorst, MD, PhD
Curt W. Burger, MD, PhD
Albert O. Brinkmann, PhD
Frans J. Huikeshoven, MD, PhD
Departments of Obstetncs and Gynecology, and Reproduction and Development, Erasmus Medical Center, Rotterdam; Department of Obstetncs and Gynecology, Ruwaard van Putten Hospital, Spijkemsse, The Netherlands
Leen J. Blok, PhD
Department of Reproduction and Development, Erasmus Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands; l.blok@erasmusmc.nl
Objective : Progesterone plays an important role in controlling proliferation and diferentiation of the human endometrium. Because there are two progesterone receptor isoforms (PRA and PRB), it was important to generate tools to be able to study the role of these two progesterone receptors separately.
Methods : Using stable transfection techniques, both human progesterone receptor isoforms (hPRA and hPRB) were reintroduced into a hPR-negative subclone of the well-differentiated endometrial cancer cell line Ishikawa. Several Ishikawa subcell lines were constructed, each expressing different levels of hPRA, hPRB, or hPRA and hPRB, respectively.
Results : These Ishikawa subcell lines showed a marked progesterone-induced growth inhibition with induction of apoptosis after long-term culture in the presence of hormone. Upon measuring gene regulation, a clear diference in regulation of expression of the selected genes by progesterone treatment was observed between the PRA-, PRB-, or PRA/B-expressing cell lines. Integrin ß34 (ITGB4) was only regulated in PRA-expressing cells; amphiregulin was highly regulated in PRB-expressing cells; inuslin-like gwoth factor binding protein 3 (IGFBP3) was only regulated in PRBand PRA /B-expressing cells; and metallothionein 1L (MT1L) was highly regulated in PRA/B-expressing cells. Interestingly, based on literature data, these genes can be implicated in induction of apoptosis, but are modulated here in such a way that suggests induction of resistance against apoptosis.
Conclusion : Reintroduction of PRs into Ishikawa cells rescued progesterone responsiveness in these cells. Furthermore, using these human endometrial cancer subcell lines, clear and distinct functional diferences between the PR isoforms were observed.
http://rsx.sagepub.com/cgi/content/abstract/12/4/285
Cancer Volume 83, Issue 1 , Pages 111 - 121
Published Online: 9 Nov 2000
Copyright © 1998 American Cancer Society
Original Article
Progesterone therapy for endometrial carcinoma reduces cell proliferation but does not alter apoptosis
Makoto Saegusa, M.D. *, Isao Okayasu, M.D.
Department of Pathology, Kitasato University School of Medicine, Kanagawa, Japan
*Correspondence to Makoto Saegusa, Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan
Abstract
BACKGROUND
Although the anticancer effects of progesterone therapy for patients with endometrial carcinoma are widely acknowledged, a detailed assessment of the resultant morphologic alterations in tumor tissue kinetics has hitherto been lacking.
METHODS
Biopsy and hysterectomy specimens of 14 endometrial carcinomas (endometrioid-type) before and during progesterone therapy were studied to clarify changes in apoptosis and cell proliferation and their relation to morphologic alterations. The extent of squamous differentiation within tumor lesions was also examined.
RESULTS
In the good-response group, tumor cells took on characteristics of normal endometrial gland cells in the secretory phase. A positive correlation between reduction in the mitotic index and the degree of morphologic alterations during hormone therapy was observed, but the frequency of apoptotic cells did not vary. In both the good-response and poor-response groups, development or enlargement of squamous areas was observed, in comparison with the initial biopsy specimens.
CONCLUSIONS
These results suggest that prolonged progesterone administration can suppress cell proliferation in endometrial carcinomas through tumor cell differentiation without alterating apoptosis, resulting in a shift in tissue kinetics toward a relative predominance of cell deletion. In addition, increases in the occurrence of squamous areas within tumors do not always appear to be related to treatment efficacy. Cancer 1998;83:111-121. © 1998 American Cancer Society.
Received: 8 July 1997; Revised: 5 December 1997; Accepted: 30 January 1997
Digital Object Identifier (DOI)
10.1002/(SICI)1097-0142(19980701)83:1<111::AID-CNCR15>3.0.CO;2-#
http://www3.interscience.wiley.com/cgi-bin/abstract/75500727/ABSTRACT?CRETRY=1&SRETRY=0
