INVESTIGADORES
CORDO RUSSO Rosalia Ines
congresos y reuniones científicas
Título:
Stat3 and ErbB-2 interaction in breast cancer metastasis.
Autor/es:
VENTURUTTI L; ROMERO L; URTREGER A; CHERVO MF; CORDO RUSSO RI; PEREYRA MG; INURRIGARRO G; DIAZ FLAQUÉ MC; SUNDBLAD V; ROA JC; GUZMÁN P; BAL DE KIER-JOFFE E; CHARREAU EH; SCHILLACI R; ELIZALDE PV
Lugar:
Philadelphia
Reunión:
Congreso; 106th Annual Meeting of the American Association for Cancer Research; 2015
Institución organizadora:
AACR
Resumen:
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