title: Progesterone receptor assembly of a transcriptional complex along with activator protein 1, signal transducer and activator of transcription 3 and ErbB-2 governs breast cancer growth and predicts response to endocrine therapy.
abstract: BACKGROUND
  The role of the progesterone receptor (PR) in breast cancer remains a major clinical challenge. Although PR induces mammary tumor growth, its presence in breast tumors is a marker of good prognosis. We investigated coordinated PR rapid and nonclassical transcriptional effects governing breast cancer growth and endocrine therapy resistance.
  
  
  METHODS
  We used breast cancer cell lines expressing wild-type and mutant PRs, cells sensitive and resistant to endocrine therapy, a variety of molecular and cellular biology approaches, in vitro proliferation studies and preclinical models to explore PR regulation of cyclin D1 expression, tumor growth, and response to endocrine therapy. We investigated the clinical significance of activator protein 1 (AP-1) and PR interaction in a cohort of 99 PR-positive breast tumors by an immunofluorescence protocol we developed. The prognostic value of AP-1/PR nuclear colocalization in overall survival (OS) was evaluated using Kaplan-Meier method, and Cox model was used to explore said colocalization as an independent prognostic factor for OS.
  
  
  RESULTS
  We demonstrated that at the cyclin D1 promoter and through coordinated rapid and transcriptional effects, progestin induces the assembly of a transcriptional complex among AP-1, Stat3, PR, and ErbB-2 which functions as an enhanceosome to drive breast cancer growth. Our studies in a cohort of human breast tumors identified PR and AP-1 nuclear interaction as a marker of good prognosis and better OS in patients treated with tamoxifen (Tam), an anti-estrogen receptor therapy. Rationale for this finding was provided by our demonstration that Tam inhibits rapid and genomic PR effects, rendering breast cancer cells sensitive to its antiproliferative effects.
  
  
  CONCLUSIONS
  We here provided novel insight into the paradox of PR action as well as new tools to identify the subgroup of ER+/PR + patients unlikely to respond to ER-targeted therapies.
authors.forename: María C
authors.initials: MC
authors.lastname: Díaz Flaqué
authors.forename: Natalia M
authors.initials: NM
authors.lastname: Galigniana
authors.forename: Wendy
authors.initials: W
authors.lastname: Béguelin
authors.forename: Rocío
authors.initials: R
authors.lastname: Vicario
authors.forename: Cecilia J
authors.initials: CJ
authors.lastname: Proietti
authors.forename: Rosalía
authors.initials: R
authors.lastname: Russo
authors.forename: Martín A
authors.initials: MA
authors.lastname: Rivas
authors.forename: Mercedes
authors.initials: M
authors.lastname: Tkach
authors.forename: Pablo
authors.initials: P
authors.lastname: Guzmán
authors.forename: Juan C
authors.initials: JC
authors.lastname: Roa
authors.forename: Esteban
authors.initials: E
authors.lastname: Maronna
authors.forename: Viviana
authors.initials: V
authors.lastname: Pineda
authors.forename: Sergio
authors.initials: S
authors.lastname: Muñoz
authors.forename: María
authors.initials: M
authors.lastname: Mercogliano
authors.forename: Eduardo H
authors.initials: EH
authors.lastname: Charreau
authors.forename: Patricio
authors.initials: P
authors.lastname: Yankilevich
authors.forename: Roxana
authors.initials: R
authors.lastname: Schillaci
authors.forename: Patricia V
authors.initials: PV
authors.lastname: Elizalde
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002467:Cell Nucleus / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D008807:Mice, Inbred BALB C; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D012189:Retrospective Studies; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use; D013629:Tamoxifen / Q000627:therapeutic use; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D019938:Cyclin D1; D017258:Medroxyprogesterone Acetate; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; D050796:STAT3 Transcription Factor; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D018808:Transcription Factor AP-1; C530104:CCND1 protein, human; C494087:Stat3 protein, mouse; C508053:ERBB2 protein, human