Published in
Wiley Open Access, EMBO Molecular Medicine, 9(5), p. 1335-1350, 2013
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- ORCID
- Wiley Open Access | PDF
- ORCID
- [www.ncbi.nlm.nih.gov] | PDF
- [www.researchgate.net] | PDF
- [www.ncbi.nlm.nih.gov] | PDF
- [www.ncbi.nlm.nih.gov] | PDF
- [europepmc.org] | PDF
- [dash.harvard.edu] | PDF
- [onlinelibrary.wiley.com] | PDF
- [www.pure.ed.ac.uk] | PDF
- [www.research.ed.ac.uk] | PDF
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Ret inhibition decreases growth and metastatic potential of estrogen receptor positive breast cancer cells
,
Anne Boulay,
Tim C. Roloff,
Martin Schreiber,
Neil Carragher,
Kenneth K. Macleod,
Michaela Schlederer,
Susanne Lienhard,
Lukas Kenner ,
Maria I. Torres-Arzayus,
Nancy E. Hynes
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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.