Invited Speaker, Full Lecture: Rapid Signaling by Progesterone Receptor

PATRICIA V. ELIZALDE

Washington DC, USA, June 10-13, 2009.

Congreso; -Endocrine Society Annual Meeting, Session: Extranuclear Signaling by Steroid Receptors: Rapid Signaling by Progesterone Receptor; 2009

Endocrine Society Annual Meeting

[S1-3] Rapid Signaling by Progesterone ReceptorP Elizalde. Inst de Biol y Med Experiment, Consejo Natl de Invest Científ, Buenos Aires, ArgentinaProgesterone receptor (PR) and ErbB-2, a member of the ErbBs family of receptor tyrosine kinases play important roles in breast cancer. ErbB-2 was initially described as a transmembrane receptor. However, a dramatic advance in our understanding of ErbB-2 function was the discovery of its nuclear localization and its function as a transcriptional regulator. Increasing evidence, including our own work, has shown a bidirectional crosstalk between the mechanisms by which PR and ErbBs modulate breast cancer growth. Thus, we found that progestin stimulates the rapid activation of ErbB-2 and its downstream signaling pathways, sensitizing breast cancer cells to the proliferative effects of ErbB-2. On the other hand, heregulin (HRG), a ligand of the ErbB receptors, induces the transcriptional activation of PR in breast tumors, which is a requirement for HRG-stimulated growth. In spite of the acknowledgement of this interplay between PR and ErbB-2, the identification of common downstream targets still remains elusive. Our studies revealed that signal transducer and activator of transcription 3 (Stat3) is a common downstream effector of PR and HRG/ErbB-2 signaling in breast cancer. We demonstrated that both PR and HRG/ErbB-2 induce Stat3 activation in breast tumors and that Stat3 participates in progestin- and HRG/ErbB-2-mediated breast tumor growth. We now found a novel and common mechanism of breast cancer proliferation stimulated by PR and ErbB-2. Progestin and HRG induce ErbB-2 and Stat3 nuclear translocation and a striking nuclear co-localization of both proteins in breast cancer cells. By using quantitative chromatin immunoprecipitation (ChIP) and sequential ChIP, we demonstrated progestin and HRG capacity to recruit both proteins to Stat3 binding sites in the cyclin D1 promoter. Through a series of experimental approaches including transient tranfection with cyclin D1 promoter luciferase constructs and RNA interfering-reconstitution strategies employing functional ErbB-2 and Stat3 mutants, we revealed ErbB-2 role as a transcriptional coactivator of Stat3 in progestin- and HRG-induced cyclin D1 promoter activation. One of the most exciting findings of this study was that abolishment of ErbB-2 nuclear translocation inhibits in vivo growth of breast tumors with both functional HRG/ErbB-2 and PR signaling pathways. Our results highlight Stat3 as a new target for the treatment of breast cancer resistant to both anti-hormonal, and to anti-tyrosine kinases therapies.Date: Wednesday, June 10, 2009Session Info: SYMPOSIUM SESSION: BASIC - Extranuclear Signaling by Steroid Receptors (9:30 AM-11:00 AM)Presentation Time: 09:30 AMRoom: 147AB Unless otherwise noted, all abstracts are embargoed until the time of their presentation at ENDO 09. The Endocrine Society reserves the right to lift the embargo on specific abstracts that