PDF(Pubmed)
Abstract：
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.
摘要：
三阴性乳腺癌（TNBC）是乳腺癌的一种亚型，易于发生转移和治疗抵抗。由于其侵略性和有限的靶向治疗，与其他形式的乳腺癌相比，TNBC的死亡率更高。为了开发新的TNBC治疗方案，我们对参与TNBC生长和进展的因素进行了表征。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信号通路调节。ASAH1的遗传敲除或药理学抑制抑制TNBC的生长和进展。机械上,ASAH1抑制刺激双特异性磷酸酶5（DUSP5）表达，抑制丝裂原活化蛋白激酶（MAPK）途径。此外，ASAH1和MAPK途径的药理学共定位抑制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通路的双重靶向是TNBC治疗的潜在新治疗方法.
