Abstract 2979: ElevatedNRASexpression as a potential driver of DCIS progression to basal-like invasive breast cancer

Abstract

Abstract Background: Ductal carcinoma in situ (DCIS) is the most common type of in situ premalignant breast cancers. What drives a subset of luminal DCIS to transition to basal invasive breast cancers is unclear. Basal-like invasive breast cancers are aggressive and associated with the shortest overall survival and time to distant metastasis. We have previously shown that N-Ras is highly expressed selectively in the basal-like subtypes of invasive breast cancers and can promote their growth and progression. In this study, we investigated whether NRAS expression at the DCIS stage can control transition from luminal DCIS to basal-like invasive breast cancers. Methods: Wilcoxon rank-sum test was conducted to assess the relative expression of NRAS in DCIS compared to invasive breast cancers in a patient cohort (GSE59248). NRAS levels were also determined by fluorescence in situ hybridization (FISH) in a collection of 21 patient tumor microarrays (TMAs) with concurrent normal, DCIS, and invasive breast cancer, and NRAS’s association with DCIS and invasive breast cancer was assessed by Wilcoxon signed rank test. How NRAS levels correlated with basal biomarkers in the TMAs, as well as in patient datasets GSE59248 and GSE3369 was determined by Pearson correlation. Gene expression changes in cell line were assessed by RNA-seq. Results: Invasive breast cancers showed higher NRAS mRNA levels, as compared to DCIS samples. These NRAShigh lesions were also enriched with basal-like features, such as basal gene expression signature, lower ER, higher p53 protein levels, and higher Ki67 levels. We have shown previously that N-Ras is a driver for tumor growth in SUM102 cells, which is a DCIS-like cell line model displaying basal-like features. Here we found that NRAS-silencing in these cells induced a shift to a luminal gene expression pattern as determined by PAM50. Conclusions: These data suggest that the rise of N-RAS levels in DCIS can not only mark but also control the emergence of basal-like features leading to more aggressive tumor activities. Targeting N-Ras and/or its downstream pathway may prevent the emergence of basal invasive breast cancers. Citation Format: Ze-yi Zheng, Hanan Elsarraj, Yang Hong, Jonathan T. Lei, Meenakshi Anurag, Yichao Shen, Flora Lo, Long Feng, Zifan Zhao, Xiang H. Zhang, Fariba Behbod, Eric C. Chang. ElevatedNRASexpression as a potential driver of DCIS progression to basal-like invasive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2979.