Abstract
Breast tumors contain tumorigenic cancer cells, termed "tumor-initiating cells" (TICs), which are capable of both replenishing themselves and giving rise to populations of nontumorigenic breast cancer cells (non-TICs). However, the molecular mechanisms responsible for breast tumor initiation remain poorly understood. Here we describe a chemical screening strategy to identify small molecules that enhance the effect of chemotherapeutic agents on TIC-enriched breast cancer cells. We identified proteins that interact with the lead compound C108, including the stress granule-associated protein, GTPase-activating protein (SH3 domain)-binding protein 2, G3BP2. G3BP2 regulates breast tumor initiation through the stabilization of Squamous cell carcinoma antigen recognized by T cells 3 (SART3) mRNA, which leads to increased expression of the pluripotency transcription factors Octamer-binding protein 4 (Oct-4) and Nanog Homeobox (Nanog). Our findings suggest that G3BP2 is important for the process of breast cancer initiation. Furthermore, these data suggest a possible connection between stress granule formation and tumor initiation in breast cancer cells.
Keywords:
G3BP2; breast cancer; stress granule; tumor-initiating cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Antigens, Neoplasm / biosynthesis
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Antigens, Neoplasm / genetics
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Antineoplastic Agents / isolation & purification
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Antineoplastic Agents / pharmacology
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Breast Neoplasms / etiology*
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Breast Neoplasms / genetics
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Breast Neoplasms / mortality
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Carcinogenesis*
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Cell Line, Tumor
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Cytoplasmic Granules / physiology
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Drug Resistance, Neoplasm
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Drug Screening Assays, Antitumor
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Female
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Gene Expression Regulation, Neoplastic
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Heterografts
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Humans
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Kaplan-Meier Estimate
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Nanog Homeobox Protein / metabolism
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / deficiency
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / metabolism
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Octamer Transcription Factor-3 / metabolism
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Paclitaxel / pharmacology
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RNA Interference
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RNA, Messenger / metabolism
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RNA, Neoplasm / metabolism
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RNA, Small Interfering / genetics
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RNA-Binding Proteins / biosynthesis
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RNA-Binding Proteins / genetics
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Small Molecule Libraries
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Neoplasm
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Antineoplastic Agents
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Carrier Proteins
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G3BP2 protein, human
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NANOG protein, human
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Nanog Homeobox Protein
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Neoplasm Proteins
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Octamer Transcription Factor-3
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POU5F1 protein, human
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RNA, Messenger
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RNA, Neoplasm
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RNA, Small Interfering
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RNA-Binding Proteins
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SART3 protein, human
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Small Molecule Libraries
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Paclitaxel