Schlafen 12 Slows TNBC Tumor Growth, Induces Luminal Markers, and Predicts Favorable Survival
The Schlafen 12 (SLFN12) protein regulates triple-negative breast cancer (TNBC) growth, differentiation, and proliferation. SLFN12 mRNA expression strongly correlates with TNBC patient survival. We sought to explore SLFN12 overexpression effects on in vivo human TNBC tumor xenograft growth and perfo...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/2/402 |
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| author | Sandeep K. Singhal Sarmad Al-Marsoummi Emilie E. Vomhof-DeKrey Bo Lauckner Trysten Beyer Marc D. Basson |
| author_facet | Sandeep K. Singhal Sarmad Al-Marsoummi Emilie E. Vomhof-DeKrey Bo Lauckner Trysten Beyer Marc D. Basson |
| author_sort | Sandeep K. Singhal |
| collection | DOAJ |
| description | The Schlafen 12 (SLFN12) protein regulates triple-negative breast cancer (TNBC) growth, differentiation, and proliferation. SLFN12 mRNA expression strongly correlates with TNBC patient survival. We sought to explore SLFN12 overexpression effects on in vivo human TNBC tumor xenograft growth and performed RNA-seq on xenografts to investigate related SLFN12 pathways. Stable SLFN12 overexpression reduced tumorigenesis, increased tumor latency, and reduced tumor volume. RNA-seq showed that SLFN12 overexpressing xenografts had higher luminal markers levels, suggesting that TNBC cells switched from an undifferentiated basal phenotype to a more differentiated, less aggressive luminal phenotype. SLFN12-overexpressing xenografts increased less aggressive BC markers, HER2 receptors ERBB2 and EGFR expression, which are not detectable by immunostaining in TNBC. Two cancer progression pathways, the NAD signaling pathway and the superpathway of cholesterol biosynthesis, were downregulated with SLFN12 overexpression. RNA-seq identified gene signatures associated with SLFN12 overexpression. Higher gene signature levels indicated good survival when tested on four independent BC datasets. These signatures behaved differently in African Americans than in Caucasian Americans, indicating a possible biological difference between these races that could contribute to the worse survival observed in African Americans with BC. These results suggest an increased SLFN12 expression modulates TNBC aggressiveness through a gene signature that could offer new treatment targets. |
| first_indexed | 2024-03-09T13:18:46Z |
| format | Article |
| id | doaj.art-b4e549ce55234315b3fe98a67df03b16 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T13:18:46Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-b4e549ce55234315b3fe98a67df03b162023-11-30T21:33:22ZengMDPI AGCancers2072-66942023-01-0115240210.3390/cancers15020402Schlafen 12 Slows TNBC Tumor Growth, Induces Luminal Markers, and Predicts Favorable SurvivalSandeep K. Singhal0Sarmad Al-Marsoummi1Emilie E. Vomhof-DeKrey2Bo Lauckner3Trysten Beyer4Marc D. Basson5Department of Pathology, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USADepartment of Pathology, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USADepartment of Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USADepartment of Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USADepartment of Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USADepartment of Pathology, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USAThe Schlafen 12 (SLFN12) protein regulates triple-negative breast cancer (TNBC) growth, differentiation, and proliferation. SLFN12 mRNA expression strongly correlates with TNBC patient survival. We sought to explore SLFN12 overexpression effects on in vivo human TNBC tumor xenograft growth and performed RNA-seq on xenografts to investigate related SLFN12 pathways. Stable SLFN12 overexpression reduced tumorigenesis, increased tumor latency, and reduced tumor volume. RNA-seq showed that SLFN12 overexpressing xenografts had higher luminal markers levels, suggesting that TNBC cells switched from an undifferentiated basal phenotype to a more differentiated, less aggressive luminal phenotype. SLFN12-overexpressing xenografts increased less aggressive BC markers, HER2 receptors ERBB2 and EGFR expression, which are not detectable by immunostaining in TNBC. Two cancer progression pathways, the NAD signaling pathway and the superpathway of cholesterol biosynthesis, were downregulated with SLFN12 overexpression. RNA-seq identified gene signatures associated with SLFN12 overexpression. Higher gene signature levels indicated good survival when tested on four independent BC datasets. These signatures behaved differently in African Americans than in Caucasian Americans, indicating a possible biological difference between these races that could contribute to the worse survival observed in African Americans with BC. These results suggest an increased SLFN12 expression modulates TNBC aggressiveness through a gene signature that could offer new treatment targets.https://www.mdpi.com/2072-6694/15/2/402prognostic predictorpersonalized medicinexenograftRNA sequencingrace |
| spellingShingle | Sandeep K. Singhal Sarmad Al-Marsoummi Emilie E. Vomhof-DeKrey Bo Lauckner Trysten Beyer Marc D. Basson Schlafen 12 Slows TNBC Tumor Growth, Induces Luminal Markers, and Predicts Favorable Survival Cancers prognostic predictor personalized medicine xenograft RNA sequencing race |
| title | Schlafen 12 Slows TNBC Tumor Growth, Induces Luminal Markers, and Predicts Favorable Survival |
| title_full | Schlafen 12 Slows TNBC Tumor Growth, Induces Luminal Markers, and Predicts Favorable Survival |
| title_fullStr | Schlafen 12 Slows TNBC Tumor Growth, Induces Luminal Markers, and Predicts Favorable Survival |
| title_full_unstemmed | Schlafen 12 Slows TNBC Tumor Growth, Induces Luminal Markers, and Predicts Favorable Survival |
| title_short | Schlafen 12 Slows TNBC Tumor Growth, Induces Luminal Markers, and Predicts Favorable Survival |
| title_sort | schlafen 12 slows tnbc tumor growth induces luminal markers and predicts favorable survival |
| topic | prognostic predictor personalized medicine xenograft RNA sequencing race |
| url | https://www.mdpi.com/2072-6694/15/2/402 |
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