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.
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.
Béguelin
Wendy
W
Instituto de Biología y Medicina Experimental, CONICET, Vuelta de Obligado 2490, Buenos Aires C1428ADN, Argentina.
Díaz Flaqué
María Celeste
MC
Proietti
Cecilia J
CJ
Cayrol
Florencia
F
Rivas
Martín A
MA
Tkach
Mercedes
M
Rosemblit
Cinthia
C
Tocci
Johanna M
JM
Charreau
Eduardo H
EH
Schillaci
Roxana
R
Elizalde
Patricia V
PV
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
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