title: Progesterone receptor induces ErbB-2 nuclear translocation to promote breast cancer growth via a novel transcriptional effect: ErbB-2 function as a coactivator of Stat3.
abstract: Progesterone receptor (PR) and ErbB-2 bidirectional cross talk participates in breast cancer development. Here, we identified a new mechanism of the PR and ErbB-2 interaction involving the PR induction of ErbB-2 nuclear translocation and the assembly of a transcriptional complex in which ErbB-2 acts as a coactivator of Stat3. We also highlighted that the function of ErbB-2 as a Stat3 coactivator drives progestin-induced cyclin D1 promoter activation. Notably, PR is also recruited together with Stat3 and ErbB-2 to the cyclin D1 promoter, unraveling a new and unexpected nonclassical PR genomic mechanism. The assembly of the nuclear Stat3/ErbB-2 transcriptional complex plays a key role in the proliferation of breast tumors with functional PR and ErbB-2. Our findings reveal a novel therapeutic intervention for PR- and ErbB-2-positive breast tumors via the specific blockage of ErbB-2 nuclear translocation.
authors.affiliation: Instituto de Biología y Medicina Experimental, CONICET, Vuelta de Obligado 2490, Buenos Aires C1428ADN, Argentina.
authors.forename: Wendy
authors.initials: W
authors.lastname: Béguelin
authors.forename: María Celeste
authors.initials: MC
authors.lastname: Díaz Flaqué
authors.forename: Cecilia J
authors.initials: CJ
authors.lastname: Proietti
authors.forename: Florencia
authors.initials: F
authors.lastname: Cayrol
authors.forename: Martín A
authors.initials: MA
authors.lastname: Rivas
authors.forename: Mercedes
authors.initials: M
authors.lastname: Tkach
authors.forename: Cinthia
authors.initials: C
authors.lastname: Rosemblit
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Tocci
authors.forename: Eduardo H
authors.initials: EH
authors.lastname: Charreau
authors.forename: Roxana
authors.initials: R
authors.lastname: Schillaci
authors.forename: Patricia V
authors.initials: PV
authors.lastname: Elizalde
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D055785:Gene Knockdown Techniques; D019940:Genes, bcl-1; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017258:Medroxyprogesterone Acetate / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D011372:Progestins / Q000633:toxicity; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D017258:Medroxyprogesterone Acetate; D011372:Progestins; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; C494087:Stat3 protein, mouse; C524056:Erbb2 protein, mouse