Abstract PS19-15: N-RAS as a marker for DCIS progression

Abstract

Abstract Background: Ductal carcinoma in situ (DCIS) is a key premalignant stage. Approximately 50% of the DCIS cases will advance to invasive ductal carcinoma (IDC); however, they are usually universally treated leading to overtreatment. While earlier premalignant breast lesions, such as atypical ductal hyperplasia, are nearly all luminal and positive for estrogen receptor α (ER+), up to 8% DCIS are basal-like, which is more aggressive. We have previously shown that N-Ras, which is highly expressed selectively in the basal-like subtype, can promote the growth and transforming activity of basal-like breast cancer (PMID 26166574). In this study we investigate whether NRAS expression at DCIS can promote basal-like properties and the progression to invasiveness. Methods: NRAS mRNA levels in normal, DCIS, and IDC patient-derived microarray databases and tissue microarrays (TMAs) were compared using student t-test. Correlation between NRAS mRNA levels and basal-like properties was assessed by Pearson Correlation. ER protein levels were assessed by IHC. NRAS was expressed in a luminal DCIS cell line model SUM225PE cells and the resulting cells were injected intraductally into mice to assess expression of basal-like markers and invasiveness in vivo. Conversely, NRAS expression was silenced in a DCIS-like basal-like cell line SUM102 and increased expression of luminal markers was assessed by RNA-seq and western blot. Results: In microarray databases, DCIS samples with higher NRAS mRNA levels are enriched with basal-like gene expression signature; furthermore, NRAS mRNA levels appear to increase progressively from normal to DICS and from DCIS to IDC. A similar correlation between high NRAS levels and invasiveness and high Ki67 levels in TMAs was observed by RNA FISH. High levels of NRAS mRNAs also correlated with low ER levels. Conclusions: How to identify the subset of DCIS cases that will become invasive is critical for addressing the current problem of overtreatment. Our data support the hypothesis that high N-RAS levels in DCIS mark invasiveness, by presumably inducing basal-like more aggressive tumor activities. On-going studies will further delineate whether N-Ras is also responsible for driving DCIS to the invasive state. Citation Format: Eric C Chang, Zeyi Zheng, Hanan Elsarraj, Yan Hong, Yichao Shen Shen, Flora Lo, Long Feng, Xian H.-F. Zhang, Fariba Behbod. N-RAS as a marker for DCIS progression [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-15.