Abstract 889: Dissecting the role of MYC in BRCA1-associated breast cancer

Abstract

Abstract Breast cancer is the most common cancer among women in the Western world. Approximately 8% of all breast cancer cases may be caused by inheritance of mutations in breast cancer susceptibility genes. Of these, BRCA1 is the most important one, contributing to approximately half of all familial breast cancer cases. BRCA1-related breast tumors show a triple-negative (TBNC) basal like phenotype, that correlates with aggressive characteristics and bad prognosis. A number of BRCA1 associated genes have been identified; among those MYC overexpression seems to have an important role in aggressive TBNC. In line with this, we found MYC to be frequently amplified in both mouse and human BRCA1-deficient breast cancers. Thus, evaluating the contribution of MYC to BRCA1-associated breast cancer might unravel new mechanistic insights and potentially open the way to new therapeutic approaches. To pursue this, we generated a WAPCre;Brca1F/F;Trp53F/F;Myc (WB1P-MYC) mouse model to monitor tumor development. Whereas the WAPCre;Brca1F/F;Trp53F/F (WB1P) mouse model develops tumors after 300 days, Cre-conditional overexpression of the MYC transgene leads to a dramatic acceleration in tumor development with a median survival of 100 days. Tumors of both models were histopathologically classified as solid carcinomas. Further characterization revealed that WB1P-MYC tumors show higher levels of apoptosis and DNA damage. Moreover, we also observed a strong difference in immune infiltrate between WB1P and WB1P-MYC tumors. To better characterize these differences between WB1P and WB1P-MYC tumors we obtained tumor organoids. Importantly, these tumor organoids maintained characteristics of the original tumor like Brca1, P53 deletion status and MYC overexpression. Moreover, they can be orthotopically transplanted in vivo, leading to formation of solid carcinomas. Therefore, they represent a versatile platform to test new drug combinations both in vitro and in vivo. To test if MYC overexpression is also required for maintenance of established tumors, we are developing a “double-layered” system for Cre-conditional and doxycycline-regulatable overexpression of the MYC gene in the WAPCre;Brca1F/F;Trp53F/F model. By administering doxycycline we will induce MYC only in Cre-expressing mammary epithelial cells. After tumor formation MYC will be switched-off to assess its role in tumor maintenance and progression. Furthermore, we would like to test new therapeutic approaches, like combining Myc down-regulation with administration of PARP inhibitors. In addition, tumor organoids of this inducible WB1P-MYC model will be a powerful system to study the MYC-associated phenotype, drugs combinations and forward genetic screens. Citation Format: Chiara Svetlana Brambillasca, Linda Henneman, Julian de Ruiter, Anne Paulien Drenth, Jos Jonkers. Dissecting the role of MYC in BRCA1-associated breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 889.