ES2-2: Mouse Models of Basal-Like Breast Cancer.

Abstract

Abstract Mouse models of human cancer provide powerful in vivo tools to study the mechanisms underlying drug response and acquired resistance. Once these processes are understood in sufficient detail it may be possible to design (combination) therapies that not only cause complete remissions but also eliminate remnant cells that might elicit recurrent disease. Women carrying germline mutations in BRCA1 are strongly predisposed to developing basal-like breast cancers, which frequently contain TP53 mutations. To study the role of BRCA1 loss-of-function in development of basal-like breast cancer, we and others have established human tumor xenograft models for basal-like-breast cancer as well as genetically engineered mouse models (GEMMs) for BRCA1-mutated basal-like breast cancer based on tissue-specific deletion of p53 and Brca1 [1]. The mammary tumors that arise in these mouse models show strong similarity to basal-like breast cancer with respect to expression of basal cell markers, high tumor grade, and lack of expression of hormone receptors and HER2 [2]. In addition, the BRCA1-mutated basal-like tumors in our mouse models are 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 [3]. We have successfully used the xenograft models and GEMMs of BRCA1-deficient basal-like breast cancer for preclinical evaluation of therapy response and elucidation of mechanisms of acquired drug resistance. BRCA-deficient mammary tumors are highly sensitive to PARP inhibitors and platinum drugs, but none of these drugs is capable of causing tumor eradication and all tumors grow back after drug treatment. Using functional genetic screens and mouse genetics, we found that therapy response and resistance is affected by several factors, including drug efflux transporter activity [3,4], type of BRCA1 founder mutation and 53BP1 status [5]. 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 [6], 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 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 [7].