In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 68, No. 9_Supplement ( 2008-05-15), p. 1582-1582
Abstract:
Endocrine therapy of breast cancer is effective and widely applied. In advanced disease, about half of the patients will experience a clinical benefit from tamoxifen treatment, but ultimately the disease will progress into a resistant phenotype. The molecular basis of this general failure of endocrine therapy is not understood yet. Although gene expression profiling experiments provide gene lists to identify patients who may benefit from specific treatments, these genes mostly do not define the underlying molecular mechanisms. We have executed a functional screen for the identification of BCAR genes causing anti-estrogen resistance in a human breast cancer model and evaluated their role in a large breast cancer cohort. Estrogen-dependent ZR-75-1 human breast cancer cells were subjected to insertion mutagenesis with replication-defective retroviruses and selected for proliferation in the presence of 4-hydroxy tamoxifen. In our panel of 79 tamoxifen-resistant cell lines, the target genes of the retroviruses have been identified and were functionally tested following transfection into ZR-75-1 cells. Seven BCAR genes (AKT1, AKT2, BCAR1, BCAR3, EGFR, GRB7 and TRERF1) causing the tamoxifen-resistant phenotype were identified. Furthermore, additional putative BCAR genes and loci have been pinpointed. To determine the relevance of the identified genes in clinical breast cancer, we have studied 561 estrogen receptor-positive primary breast cancers for tumor aggressiveness and tamoxifen therapy resistance. Quantitative RT-PCR of ten genes was performed to measure the tumor mRNA levels. The endpoint for tumor aggressiveness was metastasis-free survival (MFS) of a cohort of lymph node-negative patients. Therapy resistance was evaluated in a group of patients treated with tamoxifen as first-line therapy for recurrent disease and the endpoint of this analysis was progression-free survival (PFS). Statistically significant associations with MFS were found for AKT2, EGFR, TLE3 and TRERF1 mRNA levels. In multivariate analyses including the traditional prognostic factors, AKT2, EGFR and TRERF1 were independent prognostic factors for MFS and thus are associated with tumor aggressiveness. In the analyses of PFS, mRNA levels of BCAR3, ERBB2, GRB7, TLE3 and TRERF1 were associated with the duration of clinical benefit of tamoxifen therapy, independently of the classical predictive factors. Our functional screen identified a set of clinically relevant BCAR genes offering insight in the molecular and cellular pathways of breast tumor aggressiveness and tamoxifen resistance, and thereby provides novel targets for personalized treatment and prevention strategies. Supported by the Dutch Cancer Society, the Susan G Komen Breast Cancer Foundation and the Association for International Cancer Research.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2008-1582
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2008
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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