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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Cell Movement / drug effects*
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Cell Proliferation / drug effects
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ELAV-Like Protein 1 / antagonists & inhibitors*
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ELAV-Like Protein 1 / genetics
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ELAV-Like Protein 1 / metabolism
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Female
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism*
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Humans
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / prevention & control*
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Lung Neoplasms / secondary
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Mice, Inbred BALB C
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Mice, Nude
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Middle Aged
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Neoplasm Invasiveness
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Signal Transduction
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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ELAV-Like Protein 1
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ELAVL1 protein, human
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FOXQ1 protein, human
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Forkhead Transcription Factors