Stat3 Regulates ErbB-2 Expression and Co-opts Nuclear ErbB-2 Function to Induce miR-21 Expression, PDCD4 Downregulation and Breast Cancer Metastasis.

LEANDRO VENTURUTTI; LUCÍA ROMERO; ALEJANDRO URTREGER; FLORENCIA CHERVO; ROSALÍA I. CORDO RUSSO; FLORENCIA MERCOGLIANO; GLORIA INURRIGARRO; MATÍAS G. PEREYRA; CECILIA J PROIETTI; FRANCO IZZO; MARÍA C DÍAZ FLAQUÉ; VICTORIA SUNDBLAD; JUAN C. ROA; PABLO GUZMAN; ELISA BAL DE KIER JOFFÉ; EDUARDO H CHARREAU; ROXANA SCHILLACI; PATRICIA V ELIZALDE

Stevenson, WA

Encuentro; 6th PacRim Breast & Prostate Cancer Meeting; 2015

PacRim Breast and Prostate Cancer Group

Membrane overexpression of the receptor tyrosine kinase ErbB-2 (MErbB-2) accounts for a clinically aggressive breast cancer (BC) subtype (ErbB-2-positive) with increased incidence of metastases. We and others demonstrated that nuclear ErbB-2 (NErbB-2) also plays a key role in BC and is a poor prognostic factor in ErbB-2-positive tumors. The signal transducer and activator of transcription 3 (Stat3), another player in BC, has been recognized as a downstream mediator of MErbB-2 action in BC metastasis. Here, we revealed an unanticipated novel direction of the ErbB-2 and Stat3 interaction underlying BC metastasis. We found that Stat3 binds to its response elements (GAS) at the ErbB-2 promoter to up-regulate ErbB-2 transcription in metastatic, ErbB-2-positive BC. We validated these results in several BC subtypes displaying metastatic 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 recruiting ErbB-2 as its coactivator at the GAS sites in the promoter of microRNA-21 (miR-21), a metastasis-promoting miRNA. Using an ErbB-2 nuclear localization domain mutant and a constitutively activated ErbB-2 variant, we found that NErbB-2 role as a Stat3 coactivator and also its direct role as transcription factor up-regulate miR-21 in BC. This reveals a novel function of NErbB-2 as regulator of miRNAs expression. Increased levels of miR-21, in turn, downregulate the expression of the metastasis-suppressor protein PDCD4, a validated miR-21 target. Using an in vivo model of metastatic ErbB-2-postive BC, in which we silenced Stat3 and reconstituted ErbB-2 or miR-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-positve BC metastasis.