46P ERα heterogeneous expression and the TGF-βRI status in the tumour predicted tamoxifen resistance

We have previously reported that hormone-receptor positive (HR+) breast cancer patients with the heterogeneous distribution of ERα expression in tumor tissue had poor prognosis on tamoxifen treatment. There is strong evidence that the response to endocrine therapy involves molecular crosstalk between ERα and TGF-β signaling. In this study we investigated the TGF-β family member’s expression (TGF-β, TGF-βRI, and TGF-βRII) as well as their association with distribution pattern of ERα expression in predicting tamoxifen response and survival in HR+ patients. Immunohistochemical staining for TGF-β, TGF-βRI, TGF-βRII, cyclin D1 and ERα was conducted for formalin-fixed paraffin-embedded specimens of 27 HR+ breast cancer patients with progression (distant metastases or relapse) and 95 patients with no progressive disease during adjuvant tamoxifen therapy. The primary endpoint was progression-free survival (PFS). Tamoxifen-sensitive tumors showed elevated TGF-βRI expression levels compared with tamoxifen-resistant tumors (p=0.030). TGF-βRI-positive tumors were more often associated with the homogeneous ERα expression (p=0.007). There was a significant correlation between the pattern of ERα expression and TGF-βRI expression (r=0.30; p=0.007) as well as cyclin D1 expression (r=0.46; p=0.026). TGF-βRI-negative tumors with the heterogeneous ERα expression were less sensitive to tamoxifen treatment than TGF-βRI-positives with the homogeneous ERα expression pattern (p=0.049). In addition, there was a significantly higher progression rate for TGF-βRI-negative patients with whose tumors demonstrated heterogeneous ERα staining (log-rank p=0.019). These data indicate that the expression TGF-βRI is linked with the distribution pattern of ERα expression in the tumor. TGF-βRI and the pattern of ERα expression may potentially be useful biomarkers to predict the effectiveness of tamoxifen adjuvant treatment in HR+ breast cancer.