Abstract 2265: Stat3 and ErbB-2 interaction in breast cancer metastasis
Authors: Venturutti Leandro , Romero Lucía V. , Urtreger Alejandro J. , Chervo María F. , Mercogliano María F. , Cordo Russo Rosalía I. , Pereyra Matías G. , Inurrigarro Gloria , Díaz Flaqué María C. , Sunblad Victoria , Roa Juan C. , Guzmán Pablo , Bal de Kier-Joffe Elisa , Charreau Eduardo H. , Schillaci Roxana , Elizalde Patricia V. 
Published: August 2015

Metastasis is a complex multistep process, responsible for as much as 90% of cancer-related deaths, yet obtaining successful treatment for these patients remains an elusive challenge. It has long been recognized that the tyrosine kinase receptor ErbB-2 and the signal transducer and activator of transcription 3 (Stat3), two major players in the breast cancer (BC) scenario, are involved in BC metastatic dissemination through a mechanism where Stat3 acts as a downstream effector of ErbB-2 action. In addition, 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. On the other hand, microRNAs are short non-coding endogenous RNAs with regulatory functions. In particular, high levels of microRNA-21 (miR-21), a well-known oncomiR, have been reported to actively promote invasion and metastasis in BC cell lines and tissues. Here, 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. In a panel of cell lines corresponding to different BC subtypes we found that Stat3 induced ErbB-2 expression at the transcriptional level through its recruitment to response elements (called GAS) at the ErbB-2 promoter. Furthermore, we demonstrated that Stat3 co-opted NErbB-2 function, recruiting it as a coactivator, to assemble a transcriptional complex at the GAS sites of the miR-21 promoter, leading to miR-21 up-regulation. We showed that the increase in miR-21 levels resulted in the downregulation of the metastasis suppressor protein PDCD4, a well known miR-21 target. In order 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) or its expression was silenced by siRNAs. We demonstrated through reconstitution assays 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 ErbB-2 nuclear co-expression was associated with low PDCD4 expression levels, and that this correlated with the presence of nodal metastases. Our present results in experimental models and in the clinic shed light on the molecular mechanisms underlying BC metastasis and highlight targeting either Stat3 or NErbB-2 as novel therapeutic strategies for ErbB-2-positive BC patients.

#: 15-A-2849-AACR

Citation Format: Leandro Venturutti, Lucía V. Romero, Alejandro J. Urtreger, María F. Chervo, María F. Mercogliano, Rosalía I. Cordo Russo, Matías G. Pereyra, Gloria Inurrigarro, María C. Díaz Flaqué, Victoria Sunblad, Juan C. Roa, Pablo Guzmán, Elisa Bal de Kier-Joffe, Eduardo H. Charreau, Roxana Schillaci, Patricia V. Elizalde. Stat3 and ErbB-2 interaction in breast cancer metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2265. doi:10.1158/1538-7445.AM2015-2265