title: Ret inhibition decreases growth and metastatic potential of estrogen receptor positive breast cancer cells.
abstract: 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.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland.
authors.forename: Albana
authors.initials: A
authors.lastname: Gattelli
authors.forename: Ivan
authors.initials: I
authors.lastname: Nalvarte
authors.forename: Anne
authors.initials: A
authors.lastname: Boulay
authors.forename: Tim C
authors.initials: TC
authors.lastname: Roloff
authors.forename: Martin
authors.initials: M
authors.lastname: Schreiber
authors.forename: Neil
authors.initials: N
authors.lastname: Carragher
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Macleod
authors.forename: Michaela
authors.initials: M
authors.lastname: Schlederer
authors.forename: Susanne
authors.initials: S
authors.lastname: Lienhard
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.forename: Maria I
authors.initials: MI
authors.lastname: Torres-Arzayus
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Hynes
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000401:mortality / Q000503:physiopathology*; D002465:Cell Movement; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D046228:Microarray Analysis; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D051096:Proto-Oncogene Proteins c-ret / Q000096:biosynthesis*; D011960:Receptors, Estrogen / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D011960:Receptors, Estrogen; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
keywords: Fak; IL6; Ret; endocrine-therapy; metastasis