DPYSL3 modulates mitosis, migration, and epithelial-to-mesenchymal transition in claudin-low breast cancer
A Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteogenomic analysis prioritized dihydropyrimidinase-like-3 (DPYSL3) as a multilevel (RNA/protein/phosphoprotein) expression outlier specific to the claudin-low (CLOW) subset of triple-negative breast cancers. A PubMed informatics tool indicat...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2018-12, Vol.115 (51), p.E11978-E11987 |
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| creator | Matsunuma, Ryoichi Chan, Doug W. Kim, Beom-Jun Singh, Purba Han, Airi Saltzman, Alexander B. Cheng, Chonghui Lei, Jonathan T. Wang, Junkai da Silva, Leonardo Roberto Sahin, Ergun Leng, Mei Fan, Cheng Perou, Charles M. Malovannaya, Anna Ellis, Matthew J. |
| description | A Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteogenomic analysis prioritized dihydropyrimidinase-like-3 (DPYSL3) as a multilevel (RNA/protein/phosphoprotein) expression outlier specific to the claudin-low (CLOW) subset of triple-negative breast cancers. A PubMed informatics tool indicated a paucity of data in the context of breast cancer, which further prioritized DPYSL3 for study. DPYSL3 knockdown in DPYSL3-positive (DPYSL3⁺) CLOW cell lines demonstrated reduced proliferation, yet enhanced motility and increased expression of epithelial-to-mesenchymal transition (EMT) markers, suggesting that DPYSL3 is a multifunctional signaling modulator. Slower proliferation in DPYSL3-negative (DPYSL3⁻) CLOW cells was associated with accumulation of multinucleated cells, indicating a mitotic defect that was associated with a collapse of the vimentin microfilament network and increased vimentin phosphorylation. DPYSL3 also suppressed the expression of EMT regulators SNAIL and TWIST and opposed p21 activated kinase 2 (PAK2)-dependent migration. However, these EMT regulators in turn induce DPYSL3 expression, suggesting that DPYSL3 participates in negative feedback on EMT. In conclusion, DPYSL3 expression identifies CLOW tumors that will be sensitive to approaches that promote vimentin phosphorylation during mitosis and inhibitors of PAK signaling during migration and EMT. |
| doi_str_mv | 10.1073/pnas.1810598115 |
| format | Article |
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A PubMed informatics tool indicated a paucity of data in the context of breast cancer, which further prioritized DPYSL3 for study. DPYSL3 knockdown in DPYSL3-positive (DPYSL3⁺) CLOW cell lines demonstrated reduced proliferation, yet enhanced motility and increased expression of epithelial-to-mesenchymal transition (EMT) markers, suggesting that DPYSL3 is a multifunctional signaling modulator. Slower proliferation in DPYSL3-negative (DPYSL3⁻) CLOW cells was associated with accumulation of multinucleated cells, indicating a mitotic defect that was associated with a collapse of the vimentin microfilament network and increased vimentin phosphorylation. DPYSL3 also suppressed the expression of EMT regulators SNAIL and TWIST and opposed p21 activated kinase 2 (PAK2)-dependent migration. However, these EMT regulators in turn induce DPYSL3 expression, suggesting that DPYSL3 participates in negative feedback on EMT. In conclusion, DPYSL3 expression identifies CLOW tumors that will be sensitive to approaches that promote vimentin phosphorylation during mitosis and inhibitors of PAK signaling during migration and EMT.</description><identifier>ISSN: 0027-8424</identifier><identifier>ISSN: 1091-6490</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1810598115</identifier><identifier>PMID: 30498031</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Biological Sciences ; Breast cancer ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Cancer ; Cell division ; Cell Line, Tumor ; Cell Movement - physiology ; Cell Proliferation ; Claudins - metabolism ; Consortia ; Data analysis ; Dihydropyrimidinase ; Epithelial-Mesenchymal Transition - genetics ; Epithelial-Mesenchymal Transition - physiology ; Feedback, Physiological ; Female ; Gene expression ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Heterografts ; Humans ; Informatics ; Mesenchyme ; Mice ; Mice, Nude ; Mitosis ; Mitosis - physiology ; Muscle Proteins - genetics ; Muscle Proteins - metabolism ; Negative feedback ; Nuclear Proteins - metabolism ; Outliers (statistics) ; p21-activated kinase ; p21-Activated Kinases - metabolism ; Phosphorylation ; PNAS Plus ; Proteins ; Proteogenomics ; Proteomics ; Regulators ; Repressor Proteins - metabolism ; Ribonucleic acid ; RNA ; Signal Transduction ; Signaling ; Snail Family Transcription Factors - metabolism ; Triple Negative Breast Neoplasms - metabolism ; Tumors ; Twist-Related Protein 1 - metabolism ; Vimentin ; Vimentin - metabolism ; Zinc Finger E-box Binding Homeobox 2 - metabolism ; Zinc Finger E-box-Binding Homeobox 1 - metabolism</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2018-12, Vol.115 (51), p.E11978-E11987</ispartof><rights>Volumes 1–89 and 106–115, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright © 2018 the Author(s). Published by PNAS.</rights><rights>Copyright National Academy of Sciences Dec 18, 2018</rights><rights>Copyright © 2018 the Author(s). Published by PNAS. 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-52552de70081112fc9da20419b1532785574c4d5b01bf2e61b5f6e9a33ad50603</citedby><cites>FETCH-LOGICAL-c443t-52552de70081112fc9da20419b1532785574c4d5b01bf2e61b5f6e9a33ad50603</cites><orcidid>0000-0001-9827-2247 ; 0000-0003-2953-6485 ; 0000-0002-8467-8534</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26574246$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26574246$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30498031$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Matsunuma, Ryoichi</creatorcontrib><creatorcontrib>Chan, Doug W.</creatorcontrib><creatorcontrib>Kim, Beom-Jun</creatorcontrib><creatorcontrib>Singh, Purba</creatorcontrib><creatorcontrib>Han, Airi</creatorcontrib><creatorcontrib>Saltzman, Alexander B.</creatorcontrib><creatorcontrib>Cheng, Chonghui</creatorcontrib><creatorcontrib>Lei, Jonathan T.</creatorcontrib><creatorcontrib>Wang, Junkai</creatorcontrib><creatorcontrib>da Silva, Leonardo Roberto</creatorcontrib><creatorcontrib>Sahin, Ergun</creatorcontrib><creatorcontrib>Leng, Mei</creatorcontrib><creatorcontrib>Fan, Cheng</creatorcontrib><creatorcontrib>Perou, Charles M.</creatorcontrib><creatorcontrib>Malovannaya, Anna</creatorcontrib><creatorcontrib>Ellis, Matthew J.</creatorcontrib><title>DPYSL3 modulates mitosis, migration, and epithelial-to-mesenchymal transition in claudin-low breast cancer</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>A Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteogenomic analysis prioritized dihydropyrimidinase-like-3 (DPYSL3) as a multilevel (RNA/protein/phosphoprotein) expression outlier specific to the claudin-low (CLOW) subset of triple-negative breast cancers. A PubMed informatics tool indicated a paucity of data in the context of breast cancer, which further prioritized DPYSL3 for study. DPYSL3 knockdown in DPYSL3-positive (DPYSL3⁺) CLOW cell lines demonstrated reduced proliferation, yet enhanced motility and increased expression of epithelial-to-mesenchymal transition (EMT) markers, suggesting that DPYSL3 is a multifunctional signaling modulator. Slower proliferation in DPYSL3-negative (DPYSL3⁻) CLOW cells was associated with accumulation of multinucleated cells, indicating a mitotic defect that was associated with a collapse of the vimentin microfilament network and increased vimentin phosphorylation. DPYSL3 also suppressed the expression of EMT regulators SNAIL and TWIST and opposed p21 activated kinase 2 (PAK2)-dependent migration. However, these EMT regulators in turn induce DPYSL3 expression, suggesting that DPYSL3 participates in negative feedback on EMT. In conclusion, DPYSL3 expression identifies CLOW tumors that will be sensitive to approaches that promote vimentin phosphorylation during mitosis and inhibitors of PAK signaling during migration and EMT.</description><subject>Animals</subject><subject>Biological Sciences</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Cancer</subject><subject>Cell division</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - physiology</subject><subject>Cell Proliferation</subject><subject>Claudins - metabolism</subject><subject>Consortia</subject><subject>Data analysis</subject><subject>Dihydropyrimidinase</subject><subject>Epithelial-Mesenchymal Transition - genetics</subject><subject>Epithelial-Mesenchymal Transition - physiology</subject><subject>Feedback, Physiological</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Knockdown Techniques</subject><subject>Heterografts</subject><subject>Humans</subject><subject>Informatics</subject><subject>Mesenchyme</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Mitosis</subject><subject>Mitosis - physiology</subject><subject>Muscle Proteins - genetics</subject><subject>Muscle Proteins - metabolism</subject><subject>Negative feedback</subject><subject>Nuclear Proteins - metabolism</subject><subject>Outliers (statistics)</subject><subject>p21-activated kinase</subject><subject>p21-Activated Kinases - metabolism</subject><subject>Phosphorylation</subject><subject>PNAS Plus</subject><subject>Proteins</subject><subject>Proteogenomics</subject><subject>Proteomics</subject><subject>Regulators</subject><subject>Repressor Proteins - metabolism</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>Snail Family Transcription Factors - metabolism</subject><subject>Triple Negative Breast Neoplasms - metabolism</subject><subject>Tumors</subject><subject>Twist-Related Protein 1 - metabolism</subject><subject>Vimentin</subject><subject>Vimentin - metabolism</subject><subject>Zinc Finger E-box Binding Homeobox 2 - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Matsunuma, Ryoichi</au><au>Chan, Doug W.</au><au>Kim, Beom-Jun</au><au>Singh, Purba</au><au>Han, Airi</au><au>Saltzman, Alexander B.</au><au>Cheng, Chonghui</au><au>Lei, Jonathan T.</au><au>Wang, Junkai</au><au>da Silva, Leonardo Roberto</au><au>Sahin, Ergun</au><au>Leng, Mei</au><au>Fan, Cheng</au><au>Perou, Charles M.</au><au>Malovannaya, Anna</au><au>Ellis, Matthew J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>DPYSL3 modulates mitosis, migration, and epithelial-to-mesenchymal transition in claudin-low breast cancer</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2018-12-18</date><risdate>2018</risdate><volume>115</volume><issue>51</issue><spage>E11978</spage><epage>E11987</epage><pages>E11978-E11987</pages><issn>0027-8424</issn><issn>1091-6490</issn><eissn>1091-6490</eissn><abstract>A Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteogenomic analysis prioritized dihydropyrimidinase-like-3 (DPYSL3) as a multilevel (RNA/protein/phosphoprotein) expression outlier specific to the claudin-low (CLOW) subset of triple-negative breast cancers. A PubMed informatics tool indicated a paucity of data in the context of breast cancer, which further prioritized DPYSL3 for study. DPYSL3 knockdown in DPYSL3-positive (DPYSL3⁺) CLOW cell lines demonstrated reduced proliferation, yet enhanced motility and increased expression of epithelial-to-mesenchymal transition (EMT) markers, suggesting that DPYSL3 is a multifunctional signaling modulator. Slower proliferation in DPYSL3-negative (DPYSL3⁻) CLOW cells was associated with accumulation of multinucleated cells, indicating a mitotic defect that was associated with a collapse of the vimentin microfilament network and increased vimentin phosphorylation. DPYSL3 also suppressed the expression of EMT regulators SNAIL and TWIST and opposed p21 activated kinase 2 (PAK2)-dependent migration. However, these EMT regulators in turn induce DPYSL3 expression, suggesting that DPYSL3 participates in negative feedback on EMT. In conclusion, DPYSL3 expression identifies CLOW tumors that will be sensitive to approaches that promote vimentin phosphorylation during mitosis and inhibitors of PAK signaling during migration and EMT.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>30498031</pmid><doi>10.1073/pnas.1810598115</doi><orcidid>https://orcid.org/0000-0001-9827-2247</orcidid><orcidid>https://orcid.org/0000-0003-2953-6485</orcidid><orcidid>https://orcid.org/0000-0002-8467-8534</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological Sciences Breast cancer Breast Neoplasms - genetics Breast Neoplasms - metabolism Cancer Cell division Cell Line, Tumor Cell Movement - physiology Cell Proliferation Claudins - metabolism Consortia Data analysis Dihydropyrimidinase Epithelial-Mesenchymal Transition - genetics Epithelial-Mesenchymal Transition - physiology Feedback, Physiological Female Gene expression Gene Expression Regulation, Neoplastic Gene Knockdown Techniques Heterografts Humans Informatics Mesenchyme Mice Mice, Nude Mitosis Mitosis - physiology Muscle Proteins - genetics Muscle Proteins - metabolism Negative feedback Nuclear Proteins - metabolism Outliers (statistics) p21-activated kinase p21-Activated Kinases - metabolism Phosphorylation PNAS Plus Proteins Proteogenomics Proteomics Regulators Repressor Proteins - metabolism Ribonucleic acid RNA Signal Transduction Signaling Snail Family Transcription Factors - metabolism Triple Negative Breast Neoplasms - metabolism Tumors Twist-Related Protein 1 - metabolism Vimentin Vimentin - metabolism Zinc Finger E-box Binding Homeobox 2 - metabolism Zinc Finger E-box-Binding Homeobox 1 - metabolism |
| title | DPYSL3 modulates mitosis, migration, and epithelial-to-mesenchymal transition in claudin-low breast cancer |
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