Abstract
BackgroundEndocrine therapy is standard treatment for estrogen receptor (ER)-positive breast cancer. However, its efficacy is limited by intrinsic and acquired resistance. Here the potential of S100β as a biomarker and inhibition of its signaling network as a therapeutic strategy in endocrine treated patients was investigated.MethodsThe expression of S100β in tissue and serum was assessed by immunohistochemistry and an enzyme-linked immunosorbent assay, respectively. The S100β signaling network was investigated in cell line models of endocrine resistance by western blot, PCR, immunoprecipitation, and chromatin-immunoprecipitation. Endocrine resistant xenografts and tumor explants from patients with resistant tumors were treated with endocrine therapy in the presence and absence of the p-Src kinase inhibitor, dasatinib.ResultsTissue and serum levels of S100β were found to predict poor disease-free survival in endocrine-treated patients (n = 509, HR 2.32, 95% CI is 1.58–3.40, p < 0.0001 and n = 187, HR 4.009, 95% CI is 1.66–9.68, p = 0.002, respectively). Moreover, elevated levels of serum S100β detected during routine surveillance over the patient treatment period significantly associated with subsequent clinically confirmed disease recurrence (p = 0.019). In vivo studies demonstrated that endocrine treatment induced transcriptional regulation of S100β which was successfully disrupted with tyrosine kinase inhibition. In endocrine resistant xenografts and tumor explants from patients with endocrine resistant breast cancer, combined endocrine and dasatinib treatment reduced tumor proliferation and down-regulated S100β protein expression in comparison to endocrine treatment alone.ConclusionsS100β has potential as a new surveillance tool for patients with ER-positive breast cancer to monitor ongoing response to endocrine therapy. Moreover, endocrine resistant breast cancer patients with elevated S100β may benefit from combined endocrine and tyrosine-kinase inhibitor treatment.Trial registrationClinicalTrials.gov, NCT01840293). Registered on 23 April 2013. Retrospectively registered.
Highlights
Endocrine therapy is standard treatment for estrogen receptor (ER)-positive breast cancer
Dasatinib successfully inhibits p-Src expression in endocrine resistant breast cancer. (A) Expression of p-AKT, AKT, P-ERK, and ERK in panel of endocrine resistant (LY2, LetR) and sensitive (MCF-7, ARO) cell lines. (B) Tamoxifen resistant cells LY2 expressed increased levels of p-Src when treated with tamoxifen which was inhibited with PP2 (10 μM) and dasatinib (0.1 μM)
Letrozole resistant cells LetR expressed increased levels of p-Src when treated with EGF which was inhibited with PP2 (10 μM) and dasatinib (0.1 μM). (C) Interactions between steroid receptor co-activator-1 (SRC-1) and the transcription factor HOXC11 were increased by 4-OHT (1 × 10–7 M) in tamoxifen resistant LY2 cells and by EGF (10 ng/ml) in letrozole resistant LetR cells
Summary
Endocrine therapy is standard treatment for estrogen receptor (ER)-positive breast cancer. The potential of S100β as a biomarker and inhibition of its signaling network as a therapeutic strategy in endocrine treated patients was investigated. Endocrine therapies, both tamoxifen and aromatase inhibitors (AIs), successfully treat ER-positive breast cancer. Undetected resistant tumors continue to be exposed to adjuvant endocrine therapy, which can contribute to tumor progression and development of metastatic disease [1]. Understanding tumor adaptation to endocrine therapy has the potential to uncover new biomarkers of drug sensitivity and novel therapeutic targets to detect and treat endocrine resistant metastatic disease [2]. Studies from our group and others suggest that enhanced tyrosine kinase signaling, re-expression of homeobox (HOX) developmental proteins along with activation of steroid receptor co-activator-1 (SRC-1) proteins cooperate to regulate
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
