Abstract:
Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is prone to metastasis and therapy resistance. Due to its aggressive nature and limited availability of targeted therapies, TNBC isassociated with higher mortality compared to other forms of breast cancer. To develop new therapeuticoptions for TNBC, we characterized the factors involved in its growth and progression. Here, wedemonstrated that N-acylsphingosine amidohydrolase 1 (ASAH1) is overexpressed in TNBC cells and isregulated by the p53 and PI3K-AKT signaling pathways. Genetic knockdown or pharmacological inhibitionof ASAH1 suppressed TNBC growth and progression. Mechanistically, ASAH1 inhibition stimulated dualspecificityphosphatase 5 (DUSP5) expression, suppressing the mitogen-activated protein kinase (MAPK)pathway. Furthermore, pharmacological co-targeting of the ASAH1 and MAPK pathways inhibited TNBCgrowth. Collectively, we uncovered a novel role of ASAH1 in driving TNBC and identified dual targetingof the ASAH1 and MAPK pathways as a potential new therapeutic approach for TNBC treatment.
