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.

A Novel Dual Kinase Function of the RET Proto-oncogene Negatively Regulates Activating Transcription Factor 4-mediated Apoptosis

“…Conversely, disruption of RET signaling by a dominant negative truncated form of RET reduces cell viability, abolishes phosphorylation of downstream signaling molecules, reduces cell cycle progression, and stimulates apoptosis (10). RET inhibition also decreases the growth and metastatic potential of estrogen receptor-positive breast cancer cells (11). The direct transforming impact of RET as an oncogenic driver is further supported by studies in which RET transgenic mice developed a variety of malignancies (12,13).…”

Preclinical Efficacy and Safety Assessment of an Antibody–Drug Conjugate Targeting the c-RET Proto-Oncogene for Breast Carcinoma

“…Increased RET expression has been associated with decreased metastasis-free survival (HR, 2.12; P ¼ 0.0476) and overall survival (HR, 1.95; P ¼ 0.0438) in patients with breast cancer (15), and RET inhibition decreased growth and metastasis of ER þ breast cancer cells (15,16). Increased expression of RET has also been observed in primary tumors from patients who have failed tamoxifen therapy, suggesting a role for RET in endocrine resistance (17).…”

210 Genetic and epigenetic factors affect RET gene expression in breast cancer cell lines and influence survival in patients

“…In particular, RET and Gfra1 were over-expressed in a subset of ER+ tumors [28][29][30] and elevated RET levels correlated with decreased metastasis-free survival [31,32].…”