URTREGER Alejandro Jorge
congresos y reuniones científicas
Stat3 regulates ErbB-2 expression and co-opts nuclear ErbB-2 function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis
PATRICIA ELIZALDE; LEANDRO VENTURUTTI; LUCIA V. ROMERO; ALEJANDRO J. URTREGER; MARIA F. CHERVO; MARIA F. MERCOGLIANO; ROSALIA I. CORDO RUSSO; MATIAS G. PEREYRA; GLORIA INURRIGARRO; VICTORIA SUNDBLAD; MARIA C. DIAZ FLAQUE; JUAN C. ROA; PABLO GUZMAN; ELISA D. BAL DE KIER JOFFE; ROXANA SCHILLACI
Congreso; The Endocrine Societys 97th annual meeting & expo (Endo 2015); 2015
The Endocrine Society
Membrane ErbB-2 (MErbB-2) overexpression or gene amplification account for a clinically aggressive breast cancer (BC) subtype (ErbB-2 positive BC), with poor prognosis and increased incidence of metastases, We and others have also disclosed the role of nuclear ErbB-2 (NErbB-2) in BC, Whose presence we identified as a poor prognostic factor in MErbB-2-positive tumors. The signal transducer and activator of transcription 3 (Stat3), another major player scenario, has long been recognized as a downstream mediator of ErbB-2 action in BC metastatic dissemination. On the other hand, high levels of microRNA-21 (miR-21), a well-known oncomiR, have, also been reported to actively promote tumor invasion and metastasis in BC cell lines and tissues. In this study, we describe a novel hierarchical interaction between Stat3, ErbB-2 and miR-21, underlying the metastatic phenotype of ErbB-2-positive BC. We disclosed that Stat3 acts as an upstream regulator of ErbB-2 expression and function. We found, using a panel of cell lines corresponding to different BC subtypes, that Stat3 was recruited to its response elements (called GAS) at the ErbB-2 promoter, and thereby induced ErbB-2 expression at the transcriptional level. We also demonstrated that Stat3 coopted NErbB-2 function, recruiting, it as a coactivator to assemble a transcriptional complex at the GAS sites of the miR-21 promoter, which induced miR-21 expression. We showed that miR-21 increased levels, in turn, downregulated metastasis suppressor protein PDCD4, a previously validated miR-21 target. To assess the physiological relevance of our molecular findings, we developed an in vivo model of ErbB-2-overexpressing metastatic BC, in which Stat3 activation was inhibited by transfection with a Stat3 dominant negative variant (stat3Y705F) for its expression was silenced by siRNAs, Through reconstitution assays, we demonstrated that ErbB-2 and miR-21 were necessary downstream mediators of Stat3-induced metastases development. Furthermore, we explored the clinical significance of our findings in a cohort of ErbB-2-positive primary invasive BC patients and demonstrated that stat3 and ErbB2 nuclear co-expression was associated with low PDCD4 expression levels, and that this correlated with the, presence of nodal metastases, altogether, our experimental and clinical findings shed light on the molecular mechanisms underlying BC metastasis and highlight targeting, either Stat3 or ErbB-2 as novel therapeutic strategies for ErbB-2-positive Be patients.