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Progesterone-Induced Inhibition of Growth and Differential Regulation of Gene Expression in PRA- and/or PRB-Expressing Endometrial Cancer Cell Lines

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{at}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.

Key Words: hPR • hPRB • growth inhibition • apoptosis • gene expression • endometrial cancer

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