Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is prone to metastasis and therapy resistance. Owing to its aggressive nature and limited availability of targeted therapies, TNBC is associated with higher mortality as compared to other forms of breast cancer. In order to develop new therapeutic options for TNBC, we characterized the factors involved in TNBC growth and progression. Here, we demonstrate that N-acylsphingosine amidohydrolase 1 (ASAH1) is overexpressed in TNBC cells and is regulated via p53 and PI3K-AKT signaling pathways. Genetic knockdown or pharmacological inhibition of ASAH1 suppresses TNBC growth and progression. Mechanistically, ASAH1 inhibition stimulates dual-specificity phosphatase 5 (DUSP5) expression, suppressing the mitogen-activated protein kinase (MAPK) pathway. Furthermore, pharmacological cotargeting of the ASAH1 and MAPK pathways inhibits TNBC growth. Collectively, we unmasked a novel role of ASAH1 in driving TNBC and identified dual targeting of the ASAH1 and MAPK pathways as a potential new therapeutic approach for TNBC treatment.

三阴性乳腺癌（TNBC）是乳腺癌的一种亚型，容易发生转移和治疗耐药。由于其侵袭性和靶向治疗的有限性，与其他形式的乳腺癌相比，TNBC 的死亡率较高。为了开发 TNBC 的新治疗方案，我们对 TNBC 生长和进展所涉及的因素进行了表征。在这里，我们证明 N-酰基鞘氨醇酰胺水解酶 1 (ASAH1) 在 TNBC 细胞中过表达，并通过 p53 和 PI3K-AKT 信号通路进行调节。 ASAH1 的基因敲低或药理学抑制可抑制 TNBC 的生长和进展。从机制上讲，ASAH1 抑制会刺激双特异性磷酸酶 5 (DUSP5) 表达，抑制丝裂原激活蛋白激酶 (MAPK) 通路。此外，ASAH1 和 MAPK 途径的药理学共同靶向可抑制 TNBC 生长。总的来说，我们揭示了 ASAH1 在驱动 TNBC 中的新作用，并确定了 ASAH1 和 MAPK 途径的双重靶向作为 TNBC 治疗的潜在新治疗方法。