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. 2011;6(7):e22620.
doi: 10.1371/journal.pone.0022620. Epub 2011 Jul 27.

Intestinal tumorigenesis is not affected by progesterone signaling in rodent models

Jarom Heijmans  1 , Vanesa Muncan, Rutger J Jacobs, Eveline S M de Jonge-Muller, Laura Graven, Izak Biemond, Antwan G Ederveen, Patrick G Groothuis, Sietse Mosselman, James C Hardwick, Daniel W Hommes, Gijs R van den Brink
Affiliations

Intestinal tumorigenesis is not affected by progesterone signaling in rodent models

Jarom Heijmans et al. PLoS One. 2011.

Erratum in

Abstract

Clinical data suggest that progestins have chemopreventive properties in the development of colorectal cancer. We set out to examine a potential protective effect of progestins and progesterone signaling on colon cancer development. In normal and neoplastic intestinal tissue, we found that the progesterone receptor (PR) is not expressed. Expression was confined to sporadic mesenchymal cells. To analyze the influence of systemic progesterone receptor signaling, we crossed mice that lacked the progesterone receptor (PRKO) to the Apc(Min/+) mouse, a model for spontaneous intestinal polyposis. PRKO-Apc(Min/+) mice exhibited no change in polyp number, size or localization compared to Apc(Min/+). To examine effects of progestins on the intestinal epithelium that are independent of the PR, we treated mice with MPA. We found no effects of either progesterone or MPA on gross intestinal morphology or epithelial proliferation. Also, in rats treated with MPA, injection with the carcinogen azoxymethane did not result in a difference in the number or size of aberrant crypt foci, a surrogate end-point for adenoma development. We conclude that expression of the progesterone receptor is limited to cells in the intestinal mesenchyme. We did not observe any effect of progesterone receptor signaling or of progestin treatment in rodent models of intestinal tumorigenesis.

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Conflict of interest statement

Competing Interests: The authors have read the journal's policy and have the following conflicts: A.G.E., P.G.G. and S.M. are employed by Merck, Sharpe & Dohme at the Women's Health Department. This company makes for-profit hormonal preparations such as the progestin medroxyprogesterone acetate. P.G.G., A.G.E. and S.M. are researchers employed by MSD. They have contributed to this study by critical appraisal of the data and the manuscript and by sharing expert opinion. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Progesterone Receptor expression in mesenchymal cells in the intestine, not in the epithelium.
A–E) PR immunohistochemistry on the mouse colon (A) and small intestine (B,C) where rare cells express PR (arrowhead). And in an adenoma of an ApcMin/+ mouse (D). PR is widely expressed in the mouse uterus (E). F,G) In situ hybridization in mouse uterus (F) and small intestine (G). All murine tissue shown was taken from A female animal in diestrous stage, when progesterone is high . H–J) PR Expression in the human colon is located in mesenchymal cells (I) and the smooth muscle layer (J), similar to the mouse intestine. For in situ hybridization, thick (10 µm) sections were used, which makes identification of mesenchymal cells difficult. K) PR immunoblot on the mouse colon and small intestine. L) PR immunoblot on a panel of colon cancer cell lines shows no expression of either PR-A or PR-B isoform. The breast cancer cell line T47D is used as a positive control.
Figure 2
Figure 2. Lack of off-target effects from progestins on intestinal proliferation or development of acfs.
A) Treatment of a panel of colon cancer cell lines with MPA or progesterone (P4) has no effect on viability at relevant concentrations. B) BrdU incorporation in small intestine or colon after challenging female animals with MPA or progesterone (P4) for four consecutive days. C–E) Acf count in the Azoxymethane treated rat shows acf number (C), localization of acfs throughout the colon (D) and multiplicity (E) (number of crypts per acf).
Figure 3
Figure 3. The Progesterone receptor has no influence on intestinal polyposis.
A–C) Development of spontaneous polyposis in the ApcMin/+ mouse is not altered by PRKO (10 female animals per genotype).
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