Ret inhibition decreases growth and metastatic potential of estrogen receptor positive breast cancer cells.

Autor: Gattelli A; Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland., Nalvarte I, Boulay A, Roloff TC, Schreiber M, Carragher N, Macleod KK, Schlederer M, Lienhard S, Kenner L, Torres-Arzayus MI, Hynes NE
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2013 Sep; Vol. 5 (9), pp. 1335-50. Date of Electronic Publication: 2013 Jul 19.
DOI: 10.1002/emmm.201302625
Abstrakt: We show that elevated levels of Ret receptor are found in different sub-types of human breast cancers and that high Ret correlates with decreased metastasis-free survival. The role of Ret in ER+ breast cancer models was explored combining in vitro and in vivo approaches. Our analyses revealed that ligand-induced Ret activation: (i) stimulates migration of breast cancer cells; (ii) rescues cells from anti-proliferative effects of endocrine treatment and (iii) stimulates expression of cytokines in the presence of endocrine agents. Indeed, we uncovered a positive feed-forward loop between the inflammatory cytokine IL6 and Ret that links them at the expression and the functional level. In vivo inhibition of Ret in a metastatic breast cancer model inhibits tumour outgrowth and metastatic potential. Ret inhibition blocks the feed-forward loop by down-regulating Ret levels, as well as decreasing activity of Fak, an integrator of IL6-Ret signalling. Our results suggest that Ret kinase should be considered as a novel therapeutic target in subsets of breast cancer.
(© 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.)
Databáze: MEDLINE
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