Ret inhibition decreases growth and metastatic potential of estrogen receptor positive breast cancer cells
Article first published online: 19 JUL 2013
Copyright © 2013 EMBO Molecular Medicine
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 5, Issue 9, pages 1335–1350, September 2013
How to Cite
Gattelli, A., Nalvarte, I., Boulay, A., Roloff, T. C., Schreiber, M., Carragher, N., Macleod, K. K., Schlederer, M., Lienhard, S., Kenner, L., Torres-Arzayus, M. I. and Hynes, N. E. (2013), Ret inhibition decreases growth and metastatic potential of estrogen receptor positive breast cancer cells. EMBO Mol Med, 5: 1335–1350. doi: 10.1002/emmm.201302625
- Issue published online: 3 SEP 2013
- Article first published online: 19 JUL 2013
- Manuscript Accepted: 17 JUN 2013
- Manuscript Revised: 29 MAY 2013
- Manuscript Received: 11 FEB 2013
- Novartis Research Foundation
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.