Abstract 3668: Relevance of BCAR4 in tamoxifen resistance and tumor aggressiveness of breast cancer

Abstract

Abstract Background: Tamoxifen is effective in the treatment of estrogen receptor alpha (ER)-positive breast cancer. However, almost all responding patients develop resistance. Understanding the mechanisms leading to resistance is crucial for the development of more efficient therapies. In a functional screen for genes causing tamoxifen resistance, we have identified the breast cancer antiestrogen resistance 4 (BCAR4) gene. Forced expression of BCAR4 in estrogen-dependent breast cancer cell lines induced antiestrogen resistance. Objective: We explored whether BCAR4 mRNA levels in primary tumors predict tamoxifen resistance and/or tumor aggressiveness, and searched for signaling pathways involved in BCAR4-induced resistance to tamoxifen. Experimental design: BCAR4 mRNA levels were measured by quantitative RT-PCR. In 280 ER-positive primary tumors from patients receiving tamoxifen as first-line monotherapy for advanced disease, the associations between BCAR4 mRNA levels and progression-free survival (PFS) and clinical benefit were evaluated. BCAR4 mRNA levels in primary tumors from 506 patients with lymph node-negative, ER-positive cancer were evaluated for their association with distant metastasis-free survival (MFS). None of them received systemic adjuvant therapy, thereby preventing confounding effects of systemic treatment. In order to study BCAR4 function, we forced the expression of BCAR4 in estrogen-dependent ZR-75-1 breast cancer cells, and analyzed changes in phospho-protein expression. Results: In the study for the association of BCAR4 with tamoxifen resistance, high BCAR4 mRNA levels were significantly associated with a shorter PFS and poor clinical benefit (measurable tumor response or no change > 6 months). Multivariate analysis including the traditional predictive factors indicated that a high BCAR4 mRNA level is an independent predictive factor for PFS. In the assessment of tumor aggressiveness, high BCAR4 mRNA levels were associated with a shorter MFS and overall survival (OS). Multivariate analyses showed that a high BCAR4 mRNA level was an independent prognostic factor for MFS and OS. Forced expression of BCAR4 induced phosphorylation of ERBB2, ERBB3, and their down-stream mediators ERK1/2 and AKT in ZR-75-1 cells. Proliferation of these cells was inhibited by the knockdown of ERBB2 or ERBB3 with specific siRNAs, confirming the role of these receptors in BCAR4-induced tamoxifen resistance. The knockdown of ER had no effect on the proliferation of BCAR4-expressing cells, indicating that this mechanism of resistance is independent of ER signaling. Conclusions: Our data indicate that high BCAR4 mRNA levels predict resistance to tamoxifen treatment and poor outcome. The results of our experimental cell model also suggest that tumors expressing BCAR4 may rely on ERBB2/ERBB3 signaling. Therefore, patients with tumors expressing BCAR4 may be eligible to receive ERBB-targeted therapy. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3668.