Loss of B-cell translocation gene 2 in estrogen receptor–positive breast cancer and tamoxifen resistance.

Abstract

63 Background: The expression analysis in ER positive human breast cancer already demonstrated the loss of nuclear expression of BTG2, the cell cycle regulator, in 46% of tumors and showed a significant inverse correlation with cyclinD1 expression. Our analysis of Oncomine database suggested that BTG2 expression might be related to the clinical outcome in patients with tamoxifen treatment. Methods: The examinations to evaluate whether BTG2 expression affects the sensitivity against tamoxifen were conducted both in vitro and in vivo. Results: In vitro cellular proliferation assay using tamoxifen against ER positive cell lines revealed that T47D expressing high level of endogenous BTG2 showed more drug sensitivity than MCF7 expressing low level of BTG2. (MCF7; IC50=4.48uM, T47D; =1.31uM) Tetracycline-inducible BTG2 expression model was developed in MCF7 and the cellular proliferation was strongly inhibited by the concomitant administration of tetracyclin and tamoxifen in vitro. Then, the cell line was injected into the mammary fat pad of immunodeficient mice. After the tumors grew more than 125mm3, these tumor bearing mice were administered the water including tetracyclin and/or tamoxifen pellet for 3 weeks. Tumor growth ratio was significantly suppressed in the concomitant administration of tetracyclin and tamoxifen in comparison with the animal treated with single agent. (p=0.044) Consistently, tumor weight and Ki67 expression were also significantly suppressed in the mice administered both tamoxifen and tetracyclin. (BW; p=0.034, Ki67; p=0.039) The cohort of 60 patients treated with adjuvant tamoxifen monotherapy was available online. Comparison of disease-free survival (DFS) of patients with positive BTG2 expression versus patients with loss of BTG2 expression revealed an univariate association in the dataset (log-rank probability, p=0.029). Multivariate analysis indicated that BTG2 expression resulted an independent prognostic factor for DFS (HR, 0.69; 95% CI, 0.495 to 0.963; p=0.029). Conclusions: Despite further validation studies need to be conducted, BTG2 expression may be useful biomarker to identify patients appropriate for tamoxifen treatment.