Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance

Abstract

Endocrine therapy is the main therapeutic option for patients with estrogen receptor (ERa)-positive breast cancer. Resistance to this treatment is often associated with estrogen-independent activation of ERa. In this study, we show that in ERa-positive breast cancer cells, activation of the receptor tyrosine kinase RET (REarranged during Transfection) by its ligand GDNF results in increased ERa phosphorylation on Ser118 and Ser167 and estrogen-independent activation of ERa transcriptional activity. Further, we identify mTOR as a key component in this downstream signaling pathway. In tamoxifen response experiments, RET downregulation resulted in 6.2-fold increase in sensitivity of MCF7 cells to antiproliferative effects of tamoxifen, whereas GDNF stimulation had a protective effect against the drug. In tamoxifen-resistant (TAM R -1) MCF7 cells, targeting RET restored tamoxifen sensitivity. Finally, examination of two independent tissue microarrays of primary human breast cancers revealed that expression of RET protein was significantly associated with ERa-positive tumors and that in primary tumors from patients who subsequently developed invasive recurrence after adjuvant tamoxifen treatment, there was a twofold increase in the number of RET-positive tumors. Together these findings identify RET as a potentially important therapeutic target in ERa-positive breast cancers and in particular in tamoxifen-resistant tumors.

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

“…Immunohistochemical analysis of the BCCA TMA samples has demonstrated broad expression across all breast cancer subtypes, with the highest prevalence in HER2 þ and basal breast cancers. This is in contrast to previous studies that reported preferential expression of RET in ER þ breast cancer but with relatively little expression in HER2 þ and basal breast cancers (17,18,29,30). The explanation for the discordance is not clear; however, it may reflect differences in the methods (in situ hybridization vs. immunohistochemistry), protocols, reagents, sample set sizes, or patient treatment history.…”

“…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). Although the mechanism of this resistance is not well understood, RET expression is upregulated in response to estrogen treatment, and RET activation by GDNF results in increased ERa phosphorylation and activation of known ERa target genes (18).…”

Antiproliferative activity of daidzein and genistein may be related to ERα/c-erbB-2 expression in human breast cancer cells

“…ERα is a member of the steroid receptor superfamily and regulates growth, differentiation and other processes in various target cells by regulating transcriptional processes (19). It is also important in the development and progression of breast cancer (20) and is expressed in ~70% of breast cancers (21), which makes it difficult to obtain a response to cancer drug treatment.…”

RET: A Multi-Faceted Gene in Human Cancer

“…A positive correlation was demonstrated between RET over-expression and estrogen receptor-positive breast carcinoma [41,42]. Importantly, RET inhibition restored a hormone-sensitive phenotype in anti-estrogen resistant breast cancer cells [43]. Furthermore, RET protein was overexpressed in pancreatic carcinoma and involved in neural invasion of pancreatic cancer cells [44,45].…”