Abstract IA18: Genetic dissection of breast cancer development and therapy resistance in mouse models

Abstract

Abstract Genetically engineered mouse models (GEMMs) of human cancer not only permit us to gain a detailed insight into the specific genetic changes that drive tumor development and metastasis but also provide powerful 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 elicit recurrent disease. We have developed GEMMs of E-cadherin mutated lobular breast cancer. These mice develop mammary tumors that closely resemble the lobular morphology and the metastatic spectrum of the cognate tumors in humans. Using Sleeping Beauty (SB) transposon-based insertional mutagenesis in conditional E-cadherin mutant mice, we have found that heterozygous loss of MYH9 or overexpression of hyperactive truncated forms of MYPT1/2 and ASPP2 reduces actomyosin contractility and thereby promotes malignant transformation of E-cadherin-deficient mammary epithelial cells, resulting in ILC formation in mice. This work highlights actomyosin hypercontractility induced by E-cadherin loss as a critical barrier to ILC development. We have also developed several GEMMs for somatic modeling of BRCA1-mutated triple-negative breast cancer using intraductal injection of lentiviral vectors for stable overexpression of exogenous genes and CAS9-mediated disruption or APOBEC-CAS9n-UGI (BE3)-mediated base editing of endogenous genes. We have used these GEMMs to validate RB, PTEN, PIK3CA, MYC, and MCL1 as bona fide driver genes in BRCA1-associated breast cancer. Moreover, MCL1 inhibition potentiated the in vivo efficacy of the PARP inhibitor (PARPi) olaparib, underscoring the therapeutic potential of this combination for treatment of BRCA1-associated cancer patients with poor response to PARPi monotherapy. The BRCA1-deficient mammary tumors from our mouse models are characterized by genomic instability and hypersensitivity to DNA-damaging agents, including platinum drugs and PARP inhibitors. Nevertheless, none of these drugs are curative: tumors grow back after drug treatment and eventually become resistant. We found that PARPi resistance of BRCA1-deficient GEMM tumors can be induced by several mechanisms, including activation of drug efflux transporters, type of BRCA1 mutation, and loss of components of the 53BP1-RIF1-shieldin and CST complexes that govern end-protection of DNA double-strand breaks. Citation Format: Jos Jonkers. Genetic dissection of breast cancer development and therapy resistance in mouse models [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA18.