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Selective Down-Regulation of Progesterone Receptor Isoform B in Poorly Differentiated Human Endometrial Cancer Cells: Implications for Unopposed Estrogen Action¹

The Reproductive Molecular Biology Laboratory of the Department of Obstetrics and Gynecology [N. S. K., E. L., K. K. L.], the Division of Endocrinology, the Department of Medicine [N. S. K., J. R., G. O., K. B. H.], and the Department of Pathology [K. B. H.], the University of Colorado Health Sciences Center, Denver, Colorado 80262

The uterine endometrium responds to unopposed estrogen stimulation with rapid cell proliferation. Progesterone protects the endometrium against the hyperplastic effects of estradiol (E₂) through progesterone receptors (PRs), of which two isoforms are expressed: human (h) PRA and PRB. hPRB has a longer NH₂ terminus and may function differently from hPRA. Thus, the relative expression of hPRA:hPRB is likely to be important for the action of progesterone. We hypothesized that the hPRA:hPRB ratios may be abnormal in endometrial cancer, leading to a lack of normal progesterone protection against the growth-promoting effects of E₂. To test this hypothesis, well-differentiated Ishikawa endometrial cancer cells were compared to poorly differentiated Hec50 and KLE cells. Reverse transcription-PCR was chosen as a sensitive method to detect transcripts for the two forms of PR. The relative expression of PR isoforms under hormonal stimulation was determined by Western blotting. Transient transfections of hPRA and hPRB into endometrial cells allowed the evaluation of the transcriptional activity of each isoform independently on reporter gene transcription under the control of a simple progesterone response element-containing promoter. The effect of coexpressing the estrogen receptor on PR expression was also studied. Ishikawa cells (well-differentiated) express both hPRA and hPRB. Both isoforms, but predominantly hPRB, are up-regulated by E₂ and not by tamoxifen or the pure antiestrogen ICI 182,780. Hec50 and KLE cells (poorly differentiated) express only hPRA. No hPRB is present in the poorly differentiated cells, and it is not induced by estrogen receptor expression and/or estrogen treatment. In all cells, hPRB expression, whether endogenous or produced as a result of transfection, acts as a stronger transcription factor than hPRA on a simple progesterone-dependent promoter. We speculate that down-regulation of hPRB may predict for poorly differentiated endometrial cancers that do not respond to progestin therapy.

¹ These studies were supported by NIH Grants R29CA67313 (to K. K. L.), DK48238 (to K. B. H.), and CA26869 (to K. B. H.), the Cancer Research Foundation of America, and the Cancer League of Colorado.

² To whom requests for reprints should be addressed, at Box B-198, the University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, CO 80262.

Received 10/ 7/97. Accepted 3/ 4/98.

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