Inadequate DNA Damage Repair Promotes Mammary Transdifferentiation, Leading to BRCA1 Breast Cancer
Autor: | Ning Dai, Dongxi Xiang, Vladimir V. Botchkarev, Kelvin Xi Zhang, Anushka Dongre, Qing Chen, Norman Sachs, Ben Liu, Helena J. Randle, Hans Clevers, Zhe Li, Allison P. Clark, Ying Xie, David M. Livingston, Luwei Tao, Hua Wang, Aina He |
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Přispěvatelé: | Hubrecht Institute for Developmental Biology and Stem Cell Research |
Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
DNA Repair
DNA repair DNA damage Breast Neoplasms Mice Transgenic Nerve Tissue Proteins Biology Transfection General Biochemistry Genetics and Molecular Biology Article Malignant transformation 03 medical and health sciences Mice 0302 clinical medicine Mammary Glands Animal medicine Animals Humans HES1 030304 developmental biology Cisplatin 0303 health sciences BRCA1 Protein Transdifferentiation Mesenchymal stem cell Membrane Proteins Cell Differentiation Epithelial Cells Disease Models Animal Cell Transformation Neoplastic HEK293 Cells Cell Transdifferentiation NUMB Cancer research MCF-7 Cells Transcription Factor HES-1 Female 030217 neurology & neurosurgery medicine.drug DNA Damage |
Zdroj: | Cell, 178(1), 135-151.e19. Elsevier B.V. Cell |
ISSN: | 0092-8674 |
Popis: | Loss of BRCA1 p220 function often results in basal-like breast cancer (BLBC), but the underlying disease mechanism is largely opaque. In mammary epithelial cells (MECs), BRCA1 interacts with multiple proteins, including NUMB and HES1, to form complexes that participate in interstrand crosslink (ICL) DNA repair and MEC differentiation control. Unrepaired ICL damage results in aberrant transdifferentiation to a mesenchymal state of cultured, human basal-like MECs and to a basal/mesenchymal state in primary mouse luminal MECs. Loss of BRCA1, NUMB, or HES1 or chemically induced ICL damage in primary murine luminal MECs results in persistent DNA damage that triggers luminal to basal/mesenchymal transdifferentiation. In vivo single-cell analysis revealed a time-dependent evolution from normal luminal MECs to luminal progenitor-like tumor cells with basal/mesenchymal transdifferentiation during murine BRCA1 BLBC development. Growing DNA damage accompanied this malignant transformation. |
Databáze: | OpenAIRE |
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