title: Progesterone receptor blockade in human breast cancer cells decreases cell cycle progression through G2/M by repressing G2/M genes.
abstract: The synthesis of specific, potent progesterone antagonists adds potential agents to the breast cancer prevention and treatment armamentarium. The identification of individuals who will benefit from these agents will be a critical factor for their clinical success.
  
  
  
  We utilized telapristone acetate (TPA; CDB-4124) to understand the effects of progesterone receptor (PR) blockade on proliferation, apoptosis, promoter binding, cell cycle progression, and gene expression. We then identified a set of genes that overlap with human breast luteal-phase expressed genes and signify progesterone activity in both normal breast cells and breast cancer cell lines.
  
  
  
  TPA administration to T47D cells results in a 30 % decrease in cell number at 24 h, which is maintained over 72 h only in the presence of estradiol. Blockade of progesterone signaling by TPA for 24 h results in fewer cells in G2/M, attributable to decreased expression of genes that facilitate the G2/M transition. Gene expression data suggest that TPA affects several mechanisms that progesterone utilizes to control gene expression, including specific post-translational modifications, and nucleosomal organization and higher order chromatin structure, which regulate access of PR to its DNA binding sites.
  
  
  
  By comparing genes induced by the progestin R5020 in T47D cells with those increased in the luteal-phase normal breast, we have identified a set of genes that predict functional progesterone signaling in tissue. These data will facilitate an understanding of the ways in which drugs such as TPA may be utilized for the prevention, and possibly the therapy, of human breast cancer.
authors.affiliation: Department of Surgery, Feinberg School of Medicine, Northwestern University, 303 E. Superior Street, Lurie 4-111, Chicago, IL, 60611, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Clare
authors.affiliation: Department of Surgery, Feinberg School of Medicine, Northwestern University, 303 E. Superior Street, Lurie 4-111, Chicago, IL, 60611, USA.
authors.forename: Akash
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Department of Surgery, Feinberg School of Medicine, Northwestern University, 303 E. Superior Street, Lurie 4-111, Chicago, IL, 60611, USA.
authors.forename: MiRan
authors.initials: M
authors.lastname: Choi
authors.affiliation: Department of Surgery, Feinberg School of Medicine, Northwestern University, 303 E. Superior Street, Lurie 4-111, Chicago, IL, 60611, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Ranjan
authors.affiliation: Department of Surgery, Feinberg School of Medicine, Northwestern University, 303 E. Superior Street, Lurie 4-111, Chicago, IL, 60611, USA.
authors.forename: Oukseub
authors.initials: O
authors.lastname: Lee
authors.affiliation: Department of Surgery, Feinberg School of Medicine, Northwestern University, 303 E. Superior Street, Lurie 4-111, Chicago, IL, 60611, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Surgery, Feinberg School of Medicine, Northwestern University, 303 E. Superior Street, Lurie 4-111, Chicago, IL, 60611, USA.
authors.forename: David Z
authors.initials: DZ
authors.lastname: Ivancic
authors.affiliation: Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, 303 E. Superior Street, Lurie 4-111, Chicago, IL, 60611, USA. j-kim4@northwestern.edu.
authors.forename: J Julie
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Department of Surgery, Feinberg School of Medicine, Northwestern University, 303 E. Superior Street, Lurie 4-111, Chicago, IL, 60611, USA. s-khan2@northwestern.edu.
authors.forename: Seema A
authors.initials: SA
authors.lastname: Khan
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects*; D006801:Humans; D061986:MCF-7 Cells; D009649:Norpregnadienes / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011397:Promegestone / Q000494:pharmacology*
chemical_list: D009649:Norpregnadienes; C461063:telapristone acetate; D011397:Promegestone
keywords: Antiprogestin; Breast cancer; Cell cycle; G2/M; Luteal; Progesterone receptor; Telapristone acetate