title: Stress granule-associated protein G3BP2 regulates breast tumor initiation.
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.
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.|Department of Physiology, Vrije Universiteit Medical Center, 1081 HV Amsterdam, The Netherlands.
authors.forename: Nisha
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors.forename: Mark
authors.initials: M
authors.lastname: Badeaux
authors.affiliation: Department of Oncology, Jiangsu Province Hospital, Nanjing, Jiangsu 210029, China.
authors.forename: Yiqian
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors.forename: Kamila
authors.initials: K
authors.lastname: Naxerova
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors.forename: Dennis
authors.initials: D
authors.lastname: Sgroi
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors.forename: Lance L
authors.initials: LL
authors.lastname: Munn
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; igorg@steele.mgh.harvard.edu.
authors.forename: Igor
authors.initials: I
authors.lastname: Garkavtsev
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology; D001943:Breast Neoplasms / Q000209:etiology* / Q000235:genetics / Q000401:mortality; D063646:Carcinogenesis; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D003594:Cytoplasmic Granules / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000071317:Nanog Homeobox Protein / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D054852:Small Molecule Libraries
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D002352:Carrier Proteins; C574606:G3BP2 protein, human; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D009363:Neoplasm Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C416530:SART3 protein, human; D054852:Small Molecule Libraries; D017239:Paclitaxel
keywords: G3BP2; breast cancer; stress granule; tumor-initiating cells