title: Genome-wide progesterone receptor binding: cell type-specific and shared mechanisms in T47D breast cancer cells and primary leiomyoma cells.
abstract: BACKGROUND
  Progesterone, via its nuclear receptor (PR), exerts an overall tumorigenic effect on both uterine fibroid (leiomyoma) and breast cancer tissues, whereas the antiprogestin RU486 inhibits growth of these tissues through an unknown mechanism. Here, we determined the interaction between common or cell-specific genome-wide binding sites of PR and mRNA expression in RU486-treated uterine leiomyoma and breast cancer cells.
  
  
  RESULTS
  ChIP-sequencing revealed 31,457 and 7,034 PR-binding sites in breast cancer and uterine leiomyoma cells, respectively; 1,035 sites overlapped in both cell types. Based on the chromatin-PR interaction in both cell types, we statistically refined the consensus progesterone response element to G•ACA• • •TGT•C. We identified two striking differences between uterine leiomyoma and breast cancer cells. First, the cis-regulatory elements for HSF, TEF-1, and C/EBPα and β were statistically enriched at genomic RU486/PR-targets in uterine leiomyoma, whereas E2F, FOXO1, FOXA1, and FOXF sites were preferentially enriched in breast cancer cells. Second, 51.5% of RU486-regulated genes in breast cancer cells but only 6.6% of RU486-regulated genes in uterine leiomyoma cells contained a PR-binding site within 5 kb from their transcription start sites (TSSs), whereas 75.4% of RU486-regulated genes contained a PR-binding site farther than 50 kb from their TSSs in uterine leiomyoma cells. RU486 regulated only seven mRNAs in both cell types. Among these, adipophilin (PLIN2), a pro-differentiation gene, was induced via RU486 and PR via the same regulatory region in both cell types.
  
  
  CONCLUSIONS
  Our studies have identified molecular components in a RU486/PR-controlled gene network involved in the regulation of cell growth, cell migration, and extracellular matrix function. Tissue-specific and common patterns of genome-wide PR binding and gene regulation may determine the therapeutic effects of antiprogestins in uterine fibroids and breast cancer.
authors.affiliation: Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: Yin
authors.forename: Damian
authors.initials: D
authors.lastname: Roqueiro
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.forename: Jonas K
authors.initials: JK
authors.lastname: Owen
authors.forename: Anna
authors.initials: A
authors.lastname: Xie
authors.forename: Antonia
authors.initials: A
authors.lastname: Navarro
authors.forename: Diana
authors.initials: D
authors.lastname: Monsivais
authors.forename: John S
authors.initials: JS
authors.lastname: Coon
authors.forename: J Julie
authors.initials: JJ
authors.lastname: Kim
authors.forename: Yang
authors.initials: Y
authors.lastname: Dai
authors.forename: Serdar E
authors.initials: SE
authors.lastname: Bulun
mesh_terms: D000328:Adult; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015894:Genome, Human / Q000235:genetics*; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D007889:Leiomyoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D015735:Mifepristone / Q000494:pharmacology; D059372:Nucleotide Motifs / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D000070780:Perilipin-2; D056510:Position-Specific Scoring Matrices; D011980:Receptors, Progesterone / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics*; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D006727:Hormone Antagonists; D008565:Membrane Proteins; C000602982:PLIN2 protein, human; D000070780:Perilipin-2; D011980:Receptors, Progesterone; D015735:Mifepristone