Expression of an Oncogenic BARD1 Splice Variant Impairs Homologous Recombination and Predicts Response to PARP-1 Inhibitor Therapy in Colon Cancer
BRCA1-associated RING domain protein 1 (BARD1) stabilizes BRCA1 protein by forming a heterodimeric RING-RING complex and impacts function of BRCA1, including homologous recombination (HR) repair. Although colon cancer cells usually express wild type BRCA1, presence of an oncogenic BARD1 splice varia...
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| Veröffentlicht in: | Scientific reports 2016-05, Vol.6 (1), p.26273-26273, Article 26273 |
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| creator | Ozden, Ozkan Bishehsari, Faraz Bauer, Jessica Park, Seong-Hoon Jana, Arundhati Baik, Seung Hyun Sporn, Judith C. Staudacher, Jonas J. Yazici, Cemal Krett, Nancy Jung, Barbara |
| description | BRCA1-associated RING domain protein 1 (BARD1) stabilizes BRCA1 protein by forming a heterodimeric RING-RING complex and impacts function of BRCA1, including homologous recombination (HR) repair. Although colon cancer cells usually express wild type BRCA1, presence of an oncogenic BARD1 splice variant (SV) in select cancers may render BRCA1 dysfunctional and allow cells to become sensitive to HR targeting therapies. We previously reported association of loss of full-length (FL) BARD1 with poor prognosis in colon cancer as well as expression of various BARD1 SVs with unknown function. Here we show that loss of BARD1 function through the expression of a BARD1 SV, BARD1β, results in a more malignant phenotype with decreased RAD51 foci formation, reduced BRCA1 E3 ubiquitin ligase activity and decreased nuclear BRCA1 protein localization. BARD1β sensitizes colon cancer cells to poly ADP ribose polymerase 1 (PARP-1) inhibition even in a FL BRCA1 background. These results suggest that expression of BARD1β may serve as a future biomarker to assess suitability of colon cancers for HR targeting with PARP-1 inhibitors in treatment of advanced colon cancer. |
| doi_str_mv | 10.1038/srep26273 |
| format | Article |
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Although colon cancer cells usually express wild type BRCA1, presence of an oncogenic BARD1 splice variant (SV) in select cancers may render BRCA1 dysfunctional and allow cells to become sensitive to HR targeting therapies. We previously reported association of loss of full-length (FL) BARD1 with poor prognosis in colon cancer as well as expression of various BARD1 SVs with unknown function. Here we show that loss of BARD1 function through the expression of a BARD1 SV, BARD1β, results in a more malignant phenotype with decreased RAD51 foci formation, reduced BRCA1 E3 ubiquitin ligase activity and decreased nuclear BRCA1 protein localization. BARD1β sensitizes colon cancer cells to poly ADP ribose polymerase 1 (PARP-1) inhibition even in a FL BRCA1 background. These results suggest that expression of BARD1β may serve as a future biomarker to assess suitability of colon cancers for HR targeting with PARP-1 inhibitors in treatment of advanced colon cancer.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep26273</identifier><identifier>PMID: 27197561</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/51 ; 14 ; 14/63 ; 45/29 ; 631/337/1427/2190 ; 631/67/1504/1885/1393 ; 82 ; 82/80 ; Alternative splicing ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; BRCA1 protein ; BRCA1 Protein - genetics ; Breast cancer ; Cell Line, Tumor ; Colon cancer ; Colonic Neoplasms - drug therapy ; Colonic Neoplasms - genetics ; Colorectal cancer ; Homologous Recombination ; Humanities and Social Sciences ; Humans ; Irinotecan - pharmacology ; Irinotecan - therapeutic use ; Localization ; multidisciplinary ; Oxaliplatin - pharmacology ; Oxaliplatin - therapeutic use ; Poly(ADP-ribose) polymerase ; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use ; Protein Splicing ; Proteins ; Ribose ; Science ; Tumor Suppressor Proteins - genetics ; Tumor Suppressor Proteins - metabolism ; Ubiquitin ; Ubiquitin-protein ligase ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism ; Ubiquitination</subject><ispartof>Scientific reports, 2016-05, Vol.6 (1), p.26273-26273, Article 26273</ispartof><rights>The Author(s) 2016</rights><rights>Copyright Nature Publishing Group May 2016</rights><rights>Copyright © 2016, Macmillan Publishers Limited 2016 Macmillan Publishers Limited</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c504t-3c5abd890b09a5957dcf9962ef05173089be21ce3c19342e463fcf1de3f091163</citedby><cites>FETCH-LOGICAL-c504t-3c5abd890b09a5957dcf9962ef05173089be21ce3c19342e463fcf1de3f091163</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873788/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873788/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27197561$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ozden, Ozkan</creatorcontrib><creatorcontrib>Bishehsari, Faraz</creatorcontrib><creatorcontrib>Bauer, Jessica</creatorcontrib><creatorcontrib>Park, Seong-Hoon</creatorcontrib><creatorcontrib>Jana, Arundhati</creatorcontrib><creatorcontrib>Baik, Seung Hyun</creatorcontrib><creatorcontrib>Sporn, Judith C.</creatorcontrib><creatorcontrib>Staudacher, Jonas J.</creatorcontrib><creatorcontrib>Yazici, Cemal</creatorcontrib><creatorcontrib>Krett, Nancy</creatorcontrib><creatorcontrib>Jung, Barbara</creatorcontrib><title>Expression of an Oncogenic BARD1 Splice Variant Impairs Homologous Recombination and Predicts Response to PARP-1 Inhibitor Therapy in Colon Cancer</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>BRCA1-associated RING domain protein 1 (BARD1) stabilizes BRCA1 protein by forming a heterodimeric RING-RING complex and impacts function of BRCA1, including homologous recombination (HR) repair. Although colon cancer cells usually express wild type BRCA1, presence of an oncogenic BARD1 splice variant (SV) in select cancers may render BRCA1 dysfunctional and allow cells to become sensitive to HR targeting therapies. We previously reported association of loss of full-length (FL) BARD1 with poor prognosis in colon cancer as well as expression of various BARD1 SVs with unknown function. Here we show that loss of BARD1 function through the expression of a BARD1 SV, BARD1β, results in a more malignant phenotype with decreased RAD51 foci formation, reduced BRCA1 E3 ubiquitin ligase activity and decreased nuclear BRCA1 protein localization. BARD1β sensitizes colon cancer cells to poly ADP ribose polymerase 1 (PARP-1) inhibition even in a FL BRCA1 background. These results suggest that expression of BARD1β may serve as a future biomarker to assess suitability of colon cancers for HR targeting with PARP-1 inhibitors in treatment of advanced colon cancer.</description><subject>13</subject><subject>13/51</subject><subject>14</subject><subject>14/63</subject><subject>45/29</subject><subject>631/337/1427/2190</subject><subject>631/67/1504/1885/1393</subject><subject>82</subject><subject>82/80</subject><subject>Alternative splicing</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>BRCA1 protein</subject><subject>BRCA1 Protein - genetics</subject><subject>Breast cancer</subject><subject>Cell Line, Tumor</subject><subject>Colon cancer</subject><subject>Colonic Neoplasms - drug therapy</subject><subject>Colonic Neoplasms - genetics</subject><subject>Colorectal cancer</subject><subject>Homologous Recombination</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Irinotecan - 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metabolism</topic><topic>Ubiquitin</topic><topic>Ubiquitin-protein ligase</topic><topic>Ubiquitin-Protein Ligases - genetics</topic><topic>Ubiquitin-Protein Ligases - metabolism</topic><topic>Ubiquitination</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ozden, Ozkan</creatorcontrib><creatorcontrib>Bishehsari, Faraz</creatorcontrib><creatorcontrib>Bauer, Jessica</creatorcontrib><creatorcontrib>Park, Seong-Hoon</creatorcontrib><creatorcontrib>Jana, Arundhati</creatorcontrib><creatorcontrib>Baik, Seung Hyun</creatorcontrib><creatorcontrib>Sporn, Judith C.</creatorcontrib><creatorcontrib>Staudacher, Jonas J.</creatorcontrib><creatorcontrib>Yazici, Cemal</creatorcontrib><creatorcontrib>Krett, Nancy</creatorcontrib><creatorcontrib>Jung, Barbara</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ozden, Ozkan</au><au>Bishehsari, Faraz</au><au>Bauer, Jessica</au><au>Park, Seong-Hoon</au><au>Jana, Arundhati</au><au>Baik, Seung Hyun</au><au>Sporn, Judith C.</au><au>Staudacher, Jonas J.</au><au>Yazici, Cemal</au><au>Krett, Nancy</au><au>Jung, Barbara</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Expression of an Oncogenic BARD1 Splice Variant Impairs Homologous Recombination and Predicts Response to PARP-1 Inhibitor Therapy in Colon Cancer</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2016-05-20</date><risdate>2016</risdate><volume>6</volume><issue>1</issue><spage>26273</spage><epage>26273</epage><pages>26273-26273</pages><artnum>26273</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>BRCA1-associated RING domain protein 1 (BARD1) stabilizes BRCA1 protein by forming a heterodimeric RING-RING complex and impacts function of BRCA1, including homologous recombination (HR) repair. Although colon cancer cells usually express wild type BRCA1, presence of an oncogenic BARD1 splice variant (SV) in select cancers may render BRCA1 dysfunctional and allow cells to become sensitive to HR targeting therapies. We previously reported association of loss of full-length (FL) BARD1 with poor prognosis in colon cancer as well as expression of various BARD1 SVs with unknown function. Here we show that loss of BARD1 function through the expression of a BARD1 SV, BARD1β, results in a more malignant phenotype with decreased RAD51 foci formation, reduced BRCA1 E3 ubiquitin ligase activity and decreased nuclear BRCA1 protein localization. BARD1β sensitizes colon cancer cells to poly ADP ribose polymerase 1 (PARP-1) inhibition even in a FL BRCA1 background. These results suggest that expression of BARD1β may serve as a future biomarker to assess suitability of colon cancers for HR targeting with PARP-1 inhibitors in treatment of advanced colon cancer.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27197561</pmid><doi>10.1038/srep26273</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13 13/51 14 14/63 45/29 631/337/1427/2190 631/67/1504/1885/1393 82 82/80 Alternative splicing Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use BRCA1 protein BRCA1 Protein - genetics Breast cancer Cell Line, Tumor Colon cancer Colonic Neoplasms - drug therapy Colonic Neoplasms - genetics Colorectal cancer Homologous Recombination Humanities and Social Sciences Humans Irinotecan - pharmacology Irinotecan - therapeutic use Localization multidisciplinary Oxaliplatin - pharmacology Oxaliplatin - therapeutic use Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use Protein Splicing Proteins Ribose Science Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Ubiquitin Ubiquitin-protein ligase Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism Ubiquitination |
| title | Expression of an Oncogenic BARD1 Splice Variant Impairs Homologous Recombination and Predicts Response to PARP-1 Inhibitor Therapy in Colon Cancer |
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