miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors
Expression of BRCA1 is commonly decreased in sporadic breast tumors, and this correlates with poor prognosis of breast cancer patients. Here we show that BRCA1 transcripts are selectively enriched in the Argonaute/miR-182 complex and miR-182 downregulates BRCA1 expression. Antagonizing miR-182 enhan...
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| Vydáno v: | Molecular cell Ročník 41; číslo 2; s. 210 |
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| Hlavní autoři: | , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
United States
21.01.2011
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| Témata: | |
| ISSN: | 1097-4164, 1097-4164 |
| On-line přístup: | Zjistit podrobnosti o přístupu |
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| Abstract | Expression of BRCA1 is commonly decreased in sporadic breast tumors, and this correlates with poor prognosis of breast cancer patients. Here we show that BRCA1 transcripts are selectively enriched in the Argonaute/miR-182 complex and miR-182 downregulates BRCA1 expression. Antagonizing miR-182 enhances BRCA1 protein levels and protects them from IR-induced cell death, while overexpressing miR-182 reduces BRCA1 protein, impairs homologous recombination-mediated repair, and render cells hypersensitive to IR. The impaired DNA repair phenotype induced by miR-182 overexpression can be fully rescued by overexpressing miR-182-insensitive BRCA1. Consistent with a BRCA1-deficiency phenotype, miR-182-overexpressing breast tumor cells are hypersensitive to inhibitors of poly (ADP-ribose) polymerase 1 (PARP1). Conversely, antagonizing miR-182 enhances BRCA1 levels and induces resistance to PARP1 inhibitor. Finally, a clinical-grade PARP1 inhibitor impacts outgrowth of miR-182-expressing tumors in animal models. Together these results suggest that miR-182-mediated downregulation of BRCA1 impedes DNA repair and may impact breast cancer therapy. |
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| AbstractList | Expression of BRCA1 is commonly decreased in sporadic breast tumors, and this correlates with poor prognosis of breast cancer patients. Here we show that BRCA1 transcripts are selectively enriched in the Argonaute/miR-182 complex and miR-182 downregulates BRCA1 expression. Antagonizing miR-182 enhances BRCA1 protein levels and protects them from IR-induced cell death, while overexpressing miR-182 reduces BRCA1 protein, impairs homologous recombination-mediated repair, and render cells hypersensitive to IR. The impaired DNA repair phenotype induced by miR-182 overexpression can be fully rescued by overexpressing miR-182-insensitive BRCA1. Consistent with a BRCA1-deficiency phenotype, miR-182-overexpressing breast tumor cells are hypersensitive to inhibitors of poly (ADP-ribose) polymerase 1 (PARP1). Conversely, antagonizing miR-182 enhances BRCA1 levels and induces resistance to PARP1 inhibitor. Finally, a clinical-grade PARP1 inhibitor impacts outgrowth of miR-182-expressing tumors in animal models. Together these results suggest that miR-182-mediated downregulation of BRCA1 impedes DNA repair and may impact breast cancer therapy.Expression of BRCA1 is commonly decreased in sporadic breast tumors, and this correlates with poor prognosis of breast cancer patients. Here we show that BRCA1 transcripts are selectively enriched in the Argonaute/miR-182 complex and miR-182 downregulates BRCA1 expression. Antagonizing miR-182 enhances BRCA1 protein levels and protects them from IR-induced cell death, while overexpressing miR-182 reduces BRCA1 protein, impairs homologous recombination-mediated repair, and render cells hypersensitive to IR. The impaired DNA repair phenotype induced by miR-182 overexpression can be fully rescued by overexpressing miR-182-insensitive BRCA1. Consistent with a BRCA1-deficiency phenotype, miR-182-overexpressing breast tumor cells are hypersensitive to inhibitors of poly (ADP-ribose) polymerase 1 (PARP1). Conversely, antagonizing miR-182 enhances BRCA1 levels and induces resistance to PARP1 inhibitor. Finally, a clinical-grade PARP1 inhibitor impacts outgrowth of miR-182-expressing tumors in animal models. Together these results suggest that miR-182-mediated downregulation of BRCA1 impedes DNA repair and may impact breast cancer therapy. Expression of BRCA1 is commonly decreased in sporadic breast tumors, and this correlates with poor prognosis of breast cancer patients. Here we show that BRCA1 transcripts are selectively enriched in the Argonaute/miR-182 complex and miR-182 downregulates BRCA1 expression. Antagonizing miR-182 enhances BRCA1 protein levels and protects them from IR-induced cell death, while overexpressing miR-182 reduces BRCA1 protein, impairs homologous recombination-mediated repair, and render cells hypersensitive to IR. The impaired DNA repair phenotype induced by miR-182 overexpression can be fully rescued by overexpressing miR-182-insensitive BRCA1. Consistent with a BRCA1-deficiency phenotype, miR-182-overexpressing breast tumor cells are hypersensitive to inhibitors of poly (ADP-ribose) polymerase 1 (PARP1). Conversely, antagonizing miR-182 enhances BRCA1 levels and induces resistance to PARP1 inhibitor. Finally, a clinical-grade PARP1 inhibitor impacts outgrowth of miR-182-expressing tumors in animal models. Together these results suggest that miR-182-mediated downregulation of BRCA1 impedes DNA repair and may impact breast cancer therapy. |
| Author | Beech, John Gorospe, Myriam Pan, Yunfeng Helleday, Thomas Harris, Adrian L Weinstock, David M Abdelmohsen, Kotb Panchakshari, Rohit Chowdhury, Dipanjan Muschel, Ruth J Kulshrestha, Ritu Gottipati, Ponnari Moskwa, Patryk Buffa, Francesca M |
| Author_xml | – sequence: 1 givenname: Patryk surname: Moskwa fullname: Moskwa, Patryk organization: Department of Radiation Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA – sequence: 2 givenname: Francesca M surname: Buffa fullname: Buffa, Francesca M – sequence: 3 givenname: Yunfeng surname: Pan fullname: Pan, Yunfeng – sequence: 4 givenname: Rohit surname: Panchakshari fullname: Panchakshari, Rohit – sequence: 5 givenname: Ponnari surname: Gottipati fullname: Gottipati, Ponnari – sequence: 6 givenname: Ruth J surname: Muschel fullname: Muschel, Ruth J – sequence: 7 givenname: John surname: Beech fullname: Beech, John – sequence: 8 givenname: Ritu surname: Kulshrestha fullname: Kulshrestha, Ritu – sequence: 9 givenname: Kotb surname: Abdelmohsen fullname: Abdelmohsen, Kotb – sequence: 10 givenname: David M surname: Weinstock fullname: Weinstock, David M – sequence: 11 givenname: Myriam surname: Gorospe fullname: Gorospe, Myriam – sequence: 12 givenname: Adrian L surname: Harris fullname: Harris, Adrian L – sequence: 13 givenname: Thomas surname: Helleday fullname: Helleday, Thomas – sequence: 14 givenname: Dipanjan surname: Chowdhury fullname: Chowdhury, Dipanjan |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/21195000$$D View this record in MEDLINE/PubMed |
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| References | 21255724 - Mol Cell. 2011 Jan 21;41(2):135-7. doi: 10.1016/j.molcel.2011.01.005. Mol Cell. 2014 Jan 9;53(1):162-3 |
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| Snippet | Expression of BRCA1 is commonly decreased in sporadic breast tumors, and this correlates with poor prognosis of breast cancer patients. Here we show that BRCA1... |
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| SubjectTerms | Animals Antineoplastic Agents - pharmacology BRCA1 Protein - genetics Cell Differentiation Cell Line, Tumor DNA Breaks, Double-Stranded - radiation effects DNA Repair - drug effects Down-Regulation Humans K562 Cells Mice MicroRNAs - genetics MicroRNAs - metabolism MicroRNAs - physiology Phthalazines - pharmacology Piperazines - pharmacology Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerase Inhibitors |
| Title | miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors |
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