Abstract IA08: Studying therapy response and resistance in mouse models of breast cancer

Abstract

Abstract Women carrying germline mutations in BRCA1 are strongly predisposed to developing triple-negative breast cancers, which frequently contain TP53 mutations. To study the role of BRCA1 loss-of-function in development of triple-negative breast cancer, we have established genetically engineered mouse models (GEMMs) for BRCA1-mutated breast cancer based on cre-mediated tissue-specific deletion of p53 and Brca1. In addition to GEMMs for Brca1-null tumors, we have generated mammary tumor models carrying specific BRCA1 founder mutations (C61G, 185delAG and 5382insC). The mammary tumors that arise in these mouse models show strong similarity to BRCA1-associated breast cancer with respect to expression of basal cell markers, high tumor grade, and lack of expression of hormone receptors and ERBB2. In addition to these GEMMs, we have also established a panel of patient-derived xenograft (PDX) models for BRCA1-proficient and –deficient triple-negative breast cancer. BRCA1 deficiency in these PDX tumors is driven either by genetic mutation or by BRCA1 promoter methylation. The BRCA1-deficient tumors that arise in our various mouse models are in all cases characterized by a high degree of genomic instability and hypersensitivity to DNA-damaging agents due to loss of homology-directed double-strand break (DSB) repair. We have successfully used our GEMMs and PDX models of BRCA1-deficient breast cancer for preclinical evaluation of therapy response and elucidation of mechanisms of acquired drug resistance. BRCA1-deficient mammary tumors are highly sensitive to DNA-damaging agents such as platinum drugs and to PARP inhibitors, which indirectly induce DSBs by inhibiting DNA single-strand break repair. However, none of these drugs are capable of causing tumor eradication and all tumors grow back after drug treatment. By employing in vitro functional genetic screens and in vivo intervention studies, we found that therapy response and resistance is affected by several factors, including type of BRCA1 founder mutation, drug efflux transporter activity, and 53BP1 status. The lack of tumor eradication prompted us to look for additional drugs targeting BRCA-deficient tumors. Using a cell-based screening approach, we found that bifunctional alkylators such as nimustine may cause durable complete remission of BRCA-deficient mouse mammary tumors, suggesting that BRCA-mutated hereditary breast cancers and BRCA-like sporadic tumors may be eradicated by dose-intensive treatment with bifunctional alkylators. In support of this notion, patients with advanced breast cancers that display a BRCA1-like profile of genomic aberrations show a high complete remission rate and long progression-free survival after treatment with high-dose alkylating chemotherapy. Citation Format: Jos Jonkers. Studying therapy response and resistance in mouse models of breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr IA08.