Elevated NRAS expression during DCIS is a potential driver for progression to basal-like properties and local invasiveness
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-li...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-10-01
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| Series: | Breast Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13058-022-01565-5 |
| _version_ | 1811336352892977152 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ze-Yi Zheng |
| collection | DOAJ |
| description | 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 high 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 NRAS 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 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. |
| first_indexed | 2024-04-13T17:38:12Z |
| format | Article |
| id | doaj.art-d278c71ce3a34c93b8c92f370f7e8755 |
| institution | Directory Open Access Journal |
| issn | 1465-542X |
| language | English |
| last_indexed | 2024-04-13T17:38:12Z |
| publishDate | 2022-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj.art-d278c71ce3a34c93b8c92f370f7e87552022-12-22T02:37:18ZengBMCBreast Cancer Research1465-542X2022-10-0124111110.1186/s13058-022-01565-5Elevated NRAS expression during DCIS is a potential driver for progression to basal-like properties and local invasivenessZe-Yi Zheng0Hanan Elsarraj1Jonathan T. Lei2Yan Hong3Meenakshi Anurag4Long Feng5Hilda Kennedy6Yichao Shen7Flora Lo8Zifan Zhao9Bing Zhang10Xiang H.-F. Zhang11Ossama W. Tawfik12Fariba Behbod13Eric C. Chang14Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of MedicineDepartment of Pathology and Laboratory Medicine, University of Kansas Medical CenterLester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of MedicineDepartment of Pathology and Laboratory Medicine, University of Kansas Medical CenterLester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of MedicineLester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of MedicineLester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of MedicineLester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of MedicineLester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of MedicineLester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of MedicineLester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of MedicineLester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of MedicineMAWD Pathology Group, St. Luke’s HospitalDepartment of Pathology and Laboratory Medicine, University of Kansas Medical CenterLester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of MedicineAbstract 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 high 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 NRAS 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 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.https://doi.org/10.1186/s13058-022-01565-5Breast cancerDCISPremalignancyInvasionRas GTPase |
| spellingShingle | 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 Elevated NRAS expression during DCIS is a potential driver for progression to basal-like properties and local invasiveness Breast Cancer Research Breast cancer DCIS Premalignancy Invasion Ras GTPase |
| title | Elevated NRAS expression during DCIS is a potential driver for progression to basal-like properties and local invasiveness |
| title_full | Elevated NRAS expression during DCIS is a potential driver for progression to basal-like properties and local invasiveness |
| title_fullStr | Elevated NRAS expression during DCIS is a potential driver for progression to basal-like properties and local invasiveness |
| title_full_unstemmed | Elevated NRAS expression during DCIS is a potential driver for progression to basal-like properties and local invasiveness |
| title_short | Elevated NRAS expression during DCIS is a potential driver for progression to basal-like properties and local invasiveness |
| title_sort | elevated nras expression during dcis is a potential driver for progression to basal like properties and local invasiveness |
| topic | Breast cancer DCIS Premalignancy Invasion Ras GTPase |
| url | https://doi.org/10.1186/s13058-022-01565-5 |
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