Schlafen Family Intra-Regulation by IFN-α2 in Triple-Negative Breast Cancer
Triple-negative breast cancer (TNBC) has a poor prognosis and no targeted therapy for treatment. The Schlafen gene family, particularly SLFN12, critically mediates TNBC biology. Higher expression of SLFN12 correlates with decreased TNBC viability and increased chemosensitivity and patient survival,...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/23/5658 |
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| author | Savannah R. Brown Emilie E. Vomhof-DeKrey Sarmad Al-Marsoummi Nicholas D. Brown Kole Hermanson Marc D. Basson |
| author_facet | Savannah R. Brown Emilie E. Vomhof-DeKrey Sarmad Al-Marsoummi Nicholas D. Brown Kole Hermanson Marc D. Basson |
| author_sort | Savannah R. Brown |
| collection | DOAJ |
| description | Triple-negative breast cancer (TNBC) has a poor prognosis and no targeted therapy for treatment. The Schlafen gene family, particularly SLFN12, critically mediates TNBC biology. Higher expression of SLFN12 correlates with decreased TNBC viability and increased chemosensitivity and patient survival, yet no treatment is known to upregulate SLFN12 in TNBC. We hypothesized that Interferon-α (IFN-α2) upregulates SLFN12 in TNBC, subsequently reducing cell viability. We utilized short hairpin adenovirus to knockout SLFN12 (AdvShSLFN12) in MDA-MB-231, Hs-578T, and BT-549 TNBC cells. Cells were treated with AdvShSLFN12 and IFN-α2. After treatment, TNBC cell viability, SLFN family mRNA, and protein expression were analyzed. Treating TNBC cells with IFN-α2 increased SLFN12 expression and reduced cell viability. However, when AdvShSLFN12 knocked down SLFN12 during IFN-α2 treatment, TNBC cell viability was still reduced. We, therefore, investigated the potential involvement of other SLFN members IFN-α2 effects on cell viability. IFN-α2 increased SLFN5, SLFN12-Like, and SLFN14 but not SLFN11 or SLFN13. During AdvShSLFN12 + IFN-α2 treatment, the expressions of SLFN5, SLFN12-Like, and SLFN14 further increased. However, when siRNA knocked down SLFN5, SLFN12-Like, and SLFN14, the IFN-α2 reduction in viability was blunted. Although the interpretation of these results may be limited by the potential interactions between different siRNAs, these data suggest a complex regulatory signaling cascade among SLFN family members. Targeting this cascade to manipulate SLFN levels may, in the future, offer the potential to manipulate the chemosensitivity of TNBC tumors. |
| first_indexed | 2024-03-09T01:53:43Z |
| format | Article |
| id | doaj.art-48082bf7514c47778c4a8bb7e1cc67f1 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T01:53:43Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-48082bf7514c47778c4a8bb7e1cc67f12023-12-08T15:12:51ZengMDPI AGCancers2072-66942023-11-011523565810.3390/cancers15235658Schlafen Family Intra-Regulation by IFN-α2 in Triple-Negative Breast CancerSavannah R. Brown0Emilie E. Vomhof-DeKrey1Sarmad Al-Marsoummi2Nicholas D. Brown3Kole Hermanson4Marc 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 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 Surgery, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USADepartment of Surgery, Northeast Ohio Medical University, Rootstown, OH 44272, USATriple-negative breast cancer (TNBC) has a poor prognosis and no targeted therapy for treatment. The Schlafen gene family, particularly SLFN12, critically mediates TNBC biology. Higher expression of SLFN12 correlates with decreased TNBC viability and increased chemosensitivity and patient survival, yet no treatment is known to upregulate SLFN12 in TNBC. We hypothesized that Interferon-α (IFN-α2) upregulates SLFN12 in TNBC, subsequently reducing cell viability. We utilized short hairpin adenovirus to knockout SLFN12 (AdvShSLFN12) in MDA-MB-231, Hs-578T, and BT-549 TNBC cells. Cells were treated with AdvShSLFN12 and IFN-α2. After treatment, TNBC cell viability, SLFN family mRNA, and protein expression were analyzed. Treating TNBC cells with IFN-α2 increased SLFN12 expression and reduced cell viability. However, when AdvShSLFN12 knocked down SLFN12 during IFN-α2 treatment, TNBC cell viability was still reduced. We, therefore, investigated the potential involvement of other SLFN members IFN-α2 effects on cell viability. IFN-α2 increased SLFN5, SLFN12-Like, and SLFN14 but not SLFN11 or SLFN13. During AdvShSLFN12 + IFN-α2 treatment, the expressions of SLFN5, SLFN12-Like, and SLFN14 further increased. However, when siRNA knocked down SLFN5, SLFN12-Like, and SLFN14, the IFN-α2 reduction in viability was blunted. Although the interpretation of these results may be limited by the potential interactions between different siRNAs, these data suggest a complex regulatory signaling cascade among SLFN family members. Targeting this cascade to manipulate SLFN levels may, in the future, offer the potential to manipulate the chemosensitivity of TNBC tumors.https://www.mdpi.com/2072-6694/15/23/5658Schlafen 12TNBCIFN-?2AdvShSLFN12cell viability |
| spellingShingle | Savannah R. Brown Emilie E. Vomhof-DeKrey Sarmad Al-Marsoummi Nicholas D. Brown Kole Hermanson Marc D. Basson Schlafen Family Intra-Regulation by IFN-α2 in Triple-Negative Breast Cancer Cancers Schlafen 12 TNBC IFN-?2 AdvShSLFN12 cell viability |
| title | Schlafen Family Intra-Regulation by IFN-α2 in Triple-Negative Breast Cancer |
| title_full | Schlafen Family Intra-Regulation by IFN-α2 in Triple-Negative Breast Cancer |
| title_fullStr | Schlafen Family Intra-Regulation by IFN-α2 in Triple-Negative Breast Cancer |
| title_full_unstemmed | Schlafen Family Intra-Regulation by IFN-α2 in Triple-Negative Breast Cancer |
| title_short | Schlafen Family Intra-Regulation by IFN-α2 in Triple-Negative Breast Cancer |
| title_sort | schlafen family intra regulation by ifn α2 in triple negative breast cancer |
| topic | Schlafen 12 TNBC IFN-?2 AdvShSLFN12 cell viability |
| url | https://www.mdpi.com/2072-6694/15/23/5658 |
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