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Molecular signatures of in-situ to invasive progression for basal-like breast cancers: An integrated mouse model and human tumor study

ABSTRACT: Molecular signatures of in-situ to invasive progression for basal-like breast cancers: An integrated mouse model and human tumor study

PROVIDER: PRJNA756989 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15567129.fastq.gz	Fastqsanger.gz
	SRR15567130.fastq.gz	Fastqsanger.gz
	SRR15567131.fastq.gz	Fastqsanger.gz
	SRR15567132.fastq.gz	Fastqsanger.gz
	SRR15567133.fastq.gz	Fastqsanger.gz

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Project description: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 N-Ras 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 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 was 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 NRAShigh lesions were also enriched with basal-like features, such as basal gene expression signatures, lower ER, and higher p53 protein and Ki67 levels. We have shown previously that N-Ras drives aggressive features in DCIS-like and basal-like SUM102PT cells. Here, we found that NRAS-silencing induced a shift to a luminal gene expression pattern. Conversely, NRAS overexpression in the luminal DCIS SUM225 cells induced a basal-like gene expression pattern, as well as an epithelial-to-mesenchymal transition signature. Furthermore, these cells formed disorganized mammospheres containing cell masses with an apparent reduction in adhesion. Conclusions: These data suggest that elevated NRAS levels in DCIS is 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 N-Ras and/or downstream pathways may block disease progression for a subset of DCIS patients with high NRAS.

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Molecular signatures of in-situ to invasive progression for basal-like breast cancers: An integrated mouse model and human tumor study

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