DUSP1 protein's impact on breast cancer: Anticancer response and sensitivity to cisplatin

Abstract

Dual-Specificity Phosphatase 1 (DUSP1) modulates the activity of members of the Mitogen-Activated Protein Kinase (MAPK) family, including p38, JNK, and ERK1/2, which affects various cellular functions in cancer. Moreover, DUSP1 is known to influence the outcomes of cancer chemotherapy. This study aimed to reduce DUSP1 protein expression using CRISPR/Cas9 and siRNA and assess its effects on cell proliferation, migration, and tumor growth potential in triple-negative breast cancer (TNBC) cells. We examined the expression levels of p38, JNK, and ERK1/2, along with their phosphorylated forms, and investigated DUSP1's influence to cisplatin sensitivity. Our findings revealed that the downregulation of DUSP1 expression inhibited the proliferation, migration, and tumor growth potential of TNBC cells. Additionally, BCI, an inhibitor of DUSP1/6, demonstrated anti-proliferative effects on these cells. Decreasing the expression of DUSP1 increased the phosphorylation ratio of p38 and JNK, but not ERK1/2. Moreover, the anticancer response induced by cisplatin was enhanced by reducing DUSP1 expression or by treating the cells with BCI. Notably, cisplatin treatment increased p38 phosphorylation, which was significantly augmented by reduced DUSP1 expression. We also demonstrated that the DUSP1 inhibition-induced anticancer response in these cells predominantly relied on p38 activity. These findings contribute to a better understanding of the role of DUSP1 in breast cancer and offer insights into potential therapeutic strategies targeting DUSP1 to enhance the efficacy of cisplatin treatment. Our study highlights that decreased DUSP1 protein expression and activity mediates an anticancer response and increases the sensitivity of MDA-MB231 cells to cisplatin by regulating p38.