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Papers In Press, published online ahead of print November 20, 2001
J. Biol. Chem, 10.1074/jbc.M110090200
Submitted on October 18, 2001
Revised on November 5, 2001
Accepted on November 19, 2001

Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells

Jennifer K. Richer, Britta M. Jacobsen, Nicole G. Manning, M. Greg Abel, Douglas M. Wolf, and Kathryn B. Horwitz

Medicine, Division of Endocrinology, University of Colorado Health Sciences Center, Denver, CO 80262

Corresponding Author: jennifer.richer{at}uchsc.edu

The PR-A and PR-B isoforms of progesterone receptors (PR) have different physiological functions, and their ratio varies widely in breast cancers. To determine whether the two PR regulate different genes, we used human breast cancer cell lines engineered to express one or the other isoform. Cells were treated with progesterone in triplicate, time-separated experiments, allowing statistical analyses of microarray gene expression data. Of 94 progesterone-regulated genes, 65 are uniquely regulated by PR-B, 4 uniquely by PR-A, and only 25 by both. Almost half the genes encode proteins that are membrane-bound or involved in membrane-initiated signaling. We also find an important set of progesterone-regulated genes involved in mammary gland development and/or implicated in breast cancer. This first, large-scale study of PR gene regulation has important implications for the measurement of PR in breast cancers, and for the many clinical uses of synthetic progestins. It suggests that it is important to distinguish between the two isoforms in breast cancers; and that isoform-specific genes can be used to screen for ligands that selectively modulate the activity of PR-A or PR-B. Additionally, use of natural target genes, rather than “consensus” response elements, for transcription studies, should improve our understanding of steroid hormone action.


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