IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
artículos
Título:
Stat3 regulates ErbB-2 expression and co-opts ErbB-2 nuclear function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis
Autor/es:
VENTURUTTI L, ROMERO LV, URTREGER A, CHERVO MF, CORDO RUSSO RI, MERCOGLIANO MF, INURRIGARRO G, PEREYRA M, PROIETTI CJ, IZZO F, DÍAZ FLAQUÉ MC, SUNDBLAD V, ROA JC, GUZMÁN P, BAL DE KIER JOFFÉ ED, CHARREAU EH, SCHILLACI R, ELIZALDE PV
Revista:
ONCOGENE
Editorial:
NATURE PUBLISHING GROUP
Referencias:
Lugar: Londres; Año: 2016
ISSN:
0950-9232
Resumen:
Membrane overexpression of the receptor tyrosine kinase ErbB-2 (MErbB-2) accounts fora clinically aggressive breast cancer (BC) subtype (ErbB-2-positive) with increased incidence ofmetastases. We and others demonstrated that nuclear ErbB-2 (NErbB-2) also plays a key role inBC and is a poor prognostic factor in ErbB-2-positive tumors. The signal transducer andactivator of transcription 3 (Stat3), another player in BC, has been recognized as a downstreammediator of MErbB-2 action in BC metastasis. Here, we revealed an unanticipated noveldirection of the ErbB-2 and Stat3 interaction underlying BC metastasis. We found that Stat3binds to its response elements (GAS) at the ErbB-2 promoter to up-regulate ErbB-2 transcriptionin metastatic, ErbB-2-positive BC. We validated these results in several BC subtypes displayingmetastatic and non-metastatic ability, highlighting Stat3 general role as upstream regulator of ErbB-2 expression in BC. Moreover, we showed that Stat3 co-opts NErbB-2 function by recruitingErbB-2 as its coactivator at the GAS sites in the promoter of microRNA-21 (miR-21), ametastasis-promoting miRNA. Using an ErbB-2 nuclear localization domain mutant and aconstitutively activated ErbB-2 variant, we found that NErbB-2 role as a Stat3 coactivator and alsoits direct role as transcription factor up-regulate miR-21 in BC. This reveals a novel function ofNErbB-2 as regulator of miRNAs expression. Increased levels of miR-21, in turn, downregulate theexpression of the metastasis-suppressor protein PDCD4, a validated miR-21 target. Using an invivo model of metastatic ErbB-2-postive BC, in which we silenced Stat3 and reconstituted ErbB-2 ormiR-21 expression, we showed that both are downstream mediators of Stat3-driven metastasis.Supporting the clinical relevance of our results, we found an inverse correlation between ErbB-2/Stat3 nuclear co-expression and PDCD4 expression in ErbB-2-positive primary invasive BCs.Our findings identify Stat3 and NErbB-2 as novel therapeutic targets to inhibit ErbB-2-positive BCmetastasis.Keywords: Breast cancer metastasis, Nuclear ErbB-2, Stat3, miR-21