Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells.
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.
Richer
Jennifer K
JK
Department of Medicine/Endocrinology, University of Colorado School of Medicine, Denver, Colorado 80262, USA. jennifer.richer@uchsc.edu
Jacobsen
Britta M
BM
Manning
Nicole G
NG
Abel
M Greg
MG
Wolf
Douglas M
DM
Horwitz
Kathryn B
KB
D001943:Breast Neoplasms / Q000378:metabolism*; D002478:Cells, Cultured; D016000:Cluster Analysis; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D020411:Oligonucleotide Array Sequence Analysis; D011374:Progesterone / Q000378:metabolism*; D020033:Protein Isoforms; D011980:Receptors, Progesterone / Q000737:chemistry* / Q000378:metabolism* / Q000502:physiology*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D018076:DNA, Complementary; D020033:Protein Isoforms; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; D011374:Progesterone