Elevated NRAS Expression During DCIS Is a Potential Driver for Progression to Basal-Like Properties and Local Invasiveness

Authors

Ze-Yi Zheng
Hanan Elsarraj
Jonathan T Lei
Yan Hong
Meenakshi Anurag
Long Feng
Hilda Kennedy
Yichao Shen
Flora Lo
Zifan Zhao
Bing Zhang
Xiang H-F Zhang
Ossama W Tawfik
Fariba Behbod
Eric C Chang

Publication Date

10-18-2022

Journal

Breast Cancer Research

DOI

10.1186/s13058-022-01565-5

PMID

36258226

PMCID

PMC9578182

PubMedCentral® Posted Date

10-18-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Female, Carcinoma, Intraductal, Noninfiltrating, Ki-67 Antigen, Carcinoma, Ductal, Breast, Tumor Suppressor Protein p53, Breast Neoplasms, In Situ Hybridization, Fluorescence, Neoplasm Invasiveness, RNA, Messenger, Disease Progression, Membrane Proteins, GTP Phosphohydrolases

Abstract

BACKGROUND: Ductal carcinoma in situ (DCIS) is the most common type of in situ premalignant breast cancers. What drives DCIS to invasive breast cancer is unclear. Basal-like invasive breast cancers are aggressive. We have previously shown that NRAS is highly expressed selectively in 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 performed to assess expression of NRAS in DCIS compared to invasive breast tumors in patients. NRAS mRNA levels were also determined by fluorescence in situ hybridization in patient tumor microarrays (TMAs) with concurrent normal, DCIS, and invasive breast cancer, and association of NRAS mRNA levels with DCIS and invasive breast cancer was assessed by paired Wilcoxon signed-rank test. Pearson's correlation was calculated between NRAS mRNA levels and basal biomarkers in the TMAs, as well as in patient datasets. RNA-seq data were generated in cell lines, and unsupervised hierarchical clustering was performed after combining with RNA-seq data from a previously published patient cohort.

RESULTS: Invasive breast cancers showed higher NRAS mRNA levels compared to DCIS samples. These NRAS

CONCLUSIONS: These data suggest that elevated NRAS levels in DCIS are not only a marker but can also control the emergence of basal-like features leading to more aggressive tumor activity, thus supporting the therapeutic hypothesis that targeting NRAS and/or downstream pathways may block disease progression for a subset of DCIS patients with high NRAS.