title: TRIM28 multi-domain protein regulates cancer stem cell population in breast tumor development.
abstract: The expression of Tripartite motif-containing protein 28 (TRIM28)/Krüppel-associated box (KRAB)-associated protein 1 (KAP1), is elevated in at least 14 tumor types, including solid and hematopoietic tumors. High level of TRIM28 is associated with triple-negative subtype of breast cancer (TNBC), which shows higher aggressiveness and lower survival rates. Interestingly, TRIM28 is essential for maintaining the pluripotent phenotype in embryonic stem cells. Following on that finding, we evaluated the role of TRIM28 protein in the regulation of breast cancer stem cells (CSC) populations and tumorigenesis in vitro and in vivo. Downregulation of TRIM28 expression in xenografts led to deceased expression of pluripotency and mesenchymal markers, as well as inhibition of signaling pathways involved in the complex mechanism of CSC maintenance. Moreover, TRIM28 depletion reduced the ability of cancer cells to induce tumor growth when subcutaneously injected in limiting dilutions. Our data demonstrate that the downregulation of TRIM28 gene expression reduced the ability of CSCs to self-renew that resulted in significant reduction of tumor growth. Loss of function of TRIM28 leads to dysregulation of cell cycle, cellular response to stress, cancer cell metabolism, and inhibition of oxidative phosphorylation. All these mechanisms directly regulate maintenance of CSC population. Our original results revealed the role of the TRIM28 in regulating the CSC population in breast cancer. These findings may pave the way to novel and more effective therapies targeting cancer stem cells in breast tumors.
authors.affiliation: Laboratory for Gene Therapy, Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Poznan, Poland.|Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland.|Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Czerwińska
authors.affiliation: Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Parantu K
authors.initials: PK
authors.lastname: Shah
authors.affiliation: Laboratory for Gene Therapy, Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Poznan, Poland.|Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland.|Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Tomczak
authors.affiliation: Laboratory for Gene Therapy, Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Poznan, Poland.|Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Klimczak
authors.affiliation: Laboratory for Gene Therapy, Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Poznan, Poland.|Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Sylwia
authors.initials: S
authors.lastname: Mazurek
authors.affiliation: Faculty of Mathematics and Information Science, Warsaw University of Technology, Warsaw, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sozańska
authors.affiliation: Faculty of Mathematics and Information Science, Warsaw University of Technology, Warsaw, Poland.|Faculty of Mathematics, Informatics, and Mechanics, University of Warsaw, Warsaw, Poland.
authors.forename: Przemysław
authors.initials: P
authors.lastname: Biecek
authors.affiliation: Department of Cancer Pathology, Greater Poland Cancer Centre, Poznan, Poland.
authors.forename: Konstanty
authors.initials: K
authors.lastname: Korski
authors.affiliation: Department of Cancer Pathology, Greater Poland Cancer Centre, Poznan, Poland.
authors.forename: Violetta
authors.initials: V
authors.lastname: Filas
authors.affiliation: Laboratory for Gene Therapy, Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Poznan, Poland.|Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Mackiewicz
authors.affiliation: Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jannik N
authors.initials: JN
authors.lastname: Andersen
authors.affiliation: Laboratory for Gene Therapy, Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Poznan, Poland.|Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Wiznerowicz
mesh_terms: D000818:Animals; D015415:Biomarkers; D001943:Breast Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D004734:Energy Metabolism; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D011379:Prognosis; D016016:Proportional Hazards Models; D012008:Recurrence; D015398:Signal Transduction; D000076183:Tripartite Motif-Containing Protein 28 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology
chemical_list: D015415:Biomarkers; D000076183:Tripartite Motif-Containing Protein 28
keywords: KAP1; TRIM28; breast cancer stem cells; epigenetics; pluripotency