S100β as a serum marker in endocrine resistant breast cancer

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0836-2) contains supplementary material, which is available to authorized users.

S100B expression in breast cancer as a predictive marker for cancer metastasis

“…S100B expression was associated with a good overall survival rate in patients with ER-negative breast cancer, and a good DMFS in breast cancer patients as a whole. However, current endocrine therapy-treated patients with a high S100B expression and ER-positive breast cancer reveals poor disease-free survival (18). Based on these findings, it is suggested that ER signaling pathways may affect S100B expression and function.…”

“…By contrast, a recent study revealed that the serum levels of S100B were an independent prognostic determinant for patients with brain metastasis (17). In the serum of breast cancer patients subjected to endocrine therapy treatment, elevated levels of S100B are associated with a poor disease-free survival (18). Currently, the role of S100B in breast cancer is not well known and the association between the cell metastatic capacity and S100B has not yet been determined.…”

An immune‐related prognostic signature for predicting breast cancer recurrence

“…[33][34][35] Recent studies have also shown that S100 Calcium Binding Protein B (S100B) is upregulated in BC, melanoma, ovarian cancer, and colon adenocarcinoma. [36][37][38][39] Moreover S100B has shown potential as monitoring indicator for ER-positive BC, helping on the assessment of patients regarding to response to endocrine therapy. 36 Midkine (MDK) is an heparin-binding growth factor that is upregulated in various human malignancies and plays an important role in promoting growth, survival, and migration of cancer cells, as well as cancer angiogenesis and metastasis.…”

Epigenome-wide SRC-1–Mediated Gene Silencing Represses Cellular Differentiation in Advanced Breast Cancer

“…An LY2 luciferase cell line xenograft and patient breast cancer brain metastatic tumors (T347x and T638x) were expanded in NOD-SCID mice. The primary tumors were resected, grown on gelatin sponges (Spongostan, Johnson and Johnson) as previously described (42) and treated with estrogen combined with vehicle, 4-hydroxytamoxifen (4-OHT), RG108 and a combination of 4-OHT and RG108 for 72 hours. Following treatment, tumor pieces were formalin fixed and paraffin embedded for IHC analysis.…”