Evaluation of Schlafen Family Proteins in Triple Negative Breast Cancer

Schlafen12 (SLFN12) is a crucial protein associated with survival in triple-negative breast cancer (TNBC), where higher levels correlate with reduced cell viability, increased chemosensitivity, and patient survival. Despite its significance, no treatments currently upregulate SLFN12 in TNBC. SLFN12 causes differential expression of significant cancer genes, but their response to chemotherapy remains unknown. Our study aims to investigate if Interferon-α2 (IFN-α2) can upregulate SLFN12 in TNBC, subsequently reducing cell viability, and determine how chemotherapy effects the SLFN family and SLFN12 signature genes. IFN-α2 treatment in TNBC cells increased SLFN12 expression and reduced cell viability. Short-hairpin adenovirus was used to knockout SLFN12 (AdvShSLFN12). Treatment with paclitaxel or carboplatin paired with AdvShSLFN12 and IFN-a2 resulted in decreased SLFN12 mRNA levels but also a decrease in cell viability. This led us to explore other SLFN family members to determine if they compensate for SLFN12 loss. AdvShSLFN12 and IFN-a2 treatment resulted in an increase of SLFN5, SLFN12-Like, and SLFN14 mRNA expression. However, when siRNA was used to simultaneously knock down SLFN5, SLFN12, SLFN12-Like, and SLFN14, there was a slight recovery of the reduced viability. We overexpressed SLFN12 using a lentivirus and treated with camptothecin, paclitaxel, zoledronic acid, or carboplatin to evaluate signature cancer genes in TNBC cells. Results indicated that SLFN12 overexpression effected eight carcinogenic and SLFN family genes, notably downregulating GJB3 following each chemotherapy treatment. Together, these findings suggest a complex regulatory network among SLFN family members and SLFN signature genes, highlighting the potential for SLFN12 as a target in personalized chemotherapy for TNBC.