Abstract 408: Evidence of DLL4, NNAT, and SLC35C2 in suppression of breast cancer initiation, growth, and metastasis

Abstract

Abstract Breast cancer affects 1 in 8 women, resulting in 40,000 deaths annually. In most cases, a single cause of breast cancer cannot be found, but rather multiple environmental and genetic factors contribute to overall disease susceptibility. This, combined with complex gene interaction in both malignant tumor cells and nonmalignant tumor microenvironment (TME) cells, poses significant challenges in sifting through the many variants that contribute to the ~31% of breast cancer risk that is heritable. Here, we narrowed the regions associated with breast cancer risk on rat chromosome 3 (RNO3) by introgressing portions of RNO3 derived from the BN rat (protective strain) onto the genomic background of the SS rat (susceptible strain). These SS.BN3 congenics were then phenotyped for DMBA-induced mammary tumor incidence, latency, and multiplicity, which revealed two loci in close proximity that contribute to mammary tumor risk: chr3:95-130Mb (QTL1) and chr3: 154-177Mb (QTL2). By comparing these data with a previous study (Flister et al. Breast Cancer Res Treat. 2017 Aug;165(1):53-64.), we concluded that QTL1 is dependent on the host TME, whereas QTL2 directly modifies breast tumorigenesis and cancer cell proliferation. By combining the congenic mapping studies with genomic and transcriptomic sequencing, and functional analysis, we have now localized the top three candidate modifiers on RNO3: DLL4 (QTL1; TME modifier), NNAT (QTL2; cancer cell modifier), and SLC35C2 (QTL2; cancer cell modifier). Collectively, these data demonstrate the effects of several novel breast cancer modifiers, as well as highlight the potential interactions between modifiers of the malignant cancer cells and the nonmalignant host TME. Citation Format: Cody Plasterer, Angela Lemke, Dana Murphy, Carmen Bergom, Amit Joshi, Hallgeir Rui, Michael J. Flister. Evidence of DLL4, NNAT, and SLC35C2 in suppression of breast cancer initiation, growth, and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 408.