Abstract
Patients diagnosed with metastatic breast cancer have a dismal 5-year survival rate of only 24%. The RNA-binding protein Hu antigen R (HuR) is upregulated in breast cancer, and elevated cytoplasmic HuR correlates with high-grade tumors and poor clinical outcome of breast cancer. HuR promotes tumorigenesis by regulating numerous proto-oncogenes, growth factors, and cytokines that support major tumor hallmarks including invasion and metastasis. Here, we report a HuR inhibitor KH-3, which potently suppresses breast cancer cell growth and invasion. Furthermore, KH-3 inhibits breast cancer experimental lung metastasis, improves mouse survival, and reduces orthotopic tumor growth. Mechanistically, we identify FOXQ1 as a direct target of HuR. KH-3 disrupts HuR–FOXQ1 mRNA interaction, leading to inhibition of breast cancer invasion. Our study suggests that inhibiting HuR is a promising therapeutic strategy for lethal metastatic breast cancer.
Highlights
Patients diagnosed with metastatic breast cancer have a dismal 5-year survival rate of only 24%
As regulation of RNA stability and translation is mainly related to cytoplasmic localization of Hu antigen R (HuR), we focused on the cytoplasmic HuR expression
We examined the association of cytoplasmic HuR expression with other clinicopathologic variables
Summary
Patients diagnosed with metastatic breast cancer have a dismal 5-year survival rate of only 24%. HuR promotes tumorigenesis by regulating numerous proto-oncogenes, growth factors, and cytokines that support major tumor hallmarks including invasion and metastasis. We report a HuR inhibitor KH-3, which potently suppresses breast cancer cell growth and invasion. Cytoplasmic HuR accumulation is associated with high-grade malignancies with poor overall survival and disease-free survival, and may be an independent prognostic factor of poor clinical outcome in breast cancer[5,6,7]. Over the past two decades, numerous mRNA has been identified as HuR direct targets. These transcripts, which encode proto-oncogenes, growth factors and various cytokines, implicate in cell proliferation, survival, angiogenesis, immune recognition, invasion and metastasis[13]. Only a few of them are potently cytotoxic to cancer cells and therapeutic efficacy of HuR inhibitors was only examined in bladder cancer xenograft model[24] and colorectal cancer xenograft models[25,26,27]
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