Sustained conditional knockdown reveals intracellular bone sialoprotein as essential for breast cancer skeletal metastasis
Increased bone sialoprotein (BSP) serum levels are related to breast cancer skeletal metastasis, but their relevance is unknown. We elucidated novel intracellular BSP functions by a conditional knockdown of BSP. Conditional MDA-MB-231 subclones were equipped with a novel gene expression cassette con...
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| Veröffentlicht in: | Oncotarget 2014-07, Vol.5 (14), p.5510-5522 |
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| creator | Kovacheva, Marineta Zepp, Michael Berger, Stefan M Berger, Martin R |
| description | Increased bone sialoprotein (BSP) serum levels are related to breast cancer skeletal metastasis, but their relevance is unknown. We elucidated novel intracellular BSP functions by a conditional knockdown of BSP. Conditional MDA-MB-231 subclones were equipped with a novel gene expression cassette containing a tet-reg-ulated miRNA providing knockdown of BSP production. These clones were used to assess the effect of BSP on morphology, proliferation, migration, colony formation and gene expression in vitro, and on soft tissue and osteolytic le-sions in a xenograft model by three imaging methods. BSP knockdown caused significant anti-proliferative, anti-migratory and anti-clonogenic effects in vitro (p |
| doi_str_mv | 10.18632/oncotarget.2132 |
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We elucidated novel intracellular BSP functions by a conditional knockdown of BSP. Conditional MDA-MB-231 subclones were equipped with a novel gene expression cassette containing a tet-reg-ulated miRNA providing knockdown of BSP production. These clones were used to assess the effect of BSP on morphology, proliferation, migration, colony formation and gene expression in vitro, and on soft tissue and osteolytic le-sions in a xenograft model by three imaging methods. BSP knockdown caused significant anti-proliferative, anti-migratory and anti-clonogenic effects in vitro (p<0.001). In vivo, significant de-creases of soft tissue and osteolytic lesions (p<0.03) were recorded after 3 weeks of miRNA treatment, leading to complete remission within 6 weeks. Microarray data revealed that 0.3% of genes were modulated in response to BSP knockdown. Upregulated genes included the endoplasmic reticulum stress genes ATF3 and DDIT3, the tumor suppressor gene EGR1, ID2 (related to breast epithelial differentiation), c-FOS and SERPINB2, whereas the metastasis associated genes CD44 and IL11 were downregulated. Also, activation of apoptotic pathways was demonstrated. These results implicate that intracellular BSP is essential for breast cancer skeletal metastasis and a target for treating these lesions.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.2132</identifier><identifier>PMID: 24980816</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Animals ; Bone and Bones - metabolism ; Bone and Bones - pathology ; Bone Neoplasms - genetics ; Bone Neoplasms - metabolism ; Bone Neoplasms - secondary ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cell Line, Tumor ; Cell Movement - genetics ; Clone Cells ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Humans ; Male ; Rats ; Rats, Nude ; Research Paper ; Sialoglycoproteins - genetics ; Sialoglycoproteins - metabolism ; Transfection ; Tumor Cells, Cultured</subject><ispartof>Oncotarget, 2014-07, Vol.5 (14), p.5510-5522</ispartof><rights>Copyright: © 2014 Kovacheva et al. 2014</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c396t-ed5b01bf5abc29b8efc79efe022fc58061f74b7ae3010a541abff30e98757ccd3</citedby><cites>FETCH-LOGICAL-c396t-ed5b01bf5abc29b8efc79efe022fc58061f74b7ae3010a541abff30e98757ccd3</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/PMC4170606/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4170606/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,882,27905,27906,53772,53774</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24980816$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kovacheva, Marineta</creatorcontrib><creatorcontrib>Zepp, Michael</creatorcontrib><creatorcontrib>Berger, Stefan M</creatorcontrib><creatorcontrib>Berger, Martin R</creatorcontrib><title>Sustained conditional knockdown reveals intracellular bone sialoprotein as essential for breast cancer skeletal metastasis</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>Increased bone sialoprotein (BSP) serum levels are related to breast cancer skeletal metastasis, but their relevance is unknown. We elucidated novel intracellular BSP functions by a conditional knockdown of BSP. Conditional MDA-MB-231 subclones were equipped with a novel gene expression cassette containing a tet-reg-ulated miRNA providing knockdown of BSP production. These clones were used to assess the effect of BSP on morphology, proliferation, migration, colony formation and gene expression in vitro, and on soft tissue and osteolytic le-sions in a xenograft model by three imaging methods. BSP knockdown caused significant anti-proliferative, anti-migratory and anti-clonogenic effects in vitro (p<0.001). In vivo, significant de-creases of soft tissue and osteolytic lesions (p<0.03) were recorded after 3 weeks of miRNA treatment, leading to complete remission within 6 weeks. Microarray data revealed that 0.3% of genes were modulated in response to BSP knockdown. Upregulated genes included the endoplasmic reticulum stress genes ATF3 and DDIT3, the tumor suppressor gene EGR1, ID2 (related to breast epithelial differentiation), c-FOS and SERPINB2, whereas the metastasis associated genes CD44 and IL11 were downregulated. Also, activation of apoptotic pathways was demonstrated. These results implicate that intracellular BSP is essential for breast cancer skeletal metastasis and a target for treating these lesions.</description><subject>Animals</subject><subject>Bone and Bones - metabolism</subject><subject>Bone and Bones - pathology</subject><subject>Bone Neoplasms - genetics</subject><subject>Bone Neoplasms - metabolism</subject><subject>Bone Neoplasms - secondary</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - genetics</subject><subject>Clone Cells</subject><subject>Female</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Knockdown Techniques</subject><subject>Humans</subject><subject>Male</subject><subject>Rats</subject><subject>Rats, Nude</subject><subject>Research Paper</subject><subject>Sialoglycoproteins - genetics</subject><subject>Sialoglycoproteins - metabolism</subject><subject>Transfection</subject><subject>Tumor Cells, Cultured</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUclOAzEMjRCIVqV3Tig_MCXLbLkgoYpNqsQBOI8yGaeETpMqSYvg60kplOKDbdl-z7IfQueUTGhdcnbprHJR-jnECaOcHaEhFbnIWFHw44N8gMYhvJFkRV7VTJyiActFTWpaDtHn0zpEaSx0WDnbmWiclT1eWKcWnXu32MMGZB-wsdFLBX2_7qXHrbOAg5G9W3kXwVgsA4YQwMZUxNqlEQ8yRKykVeBxWEAPMbWWyaeNwYQzdKITM4x_4gi93N48T--z2ePdw_R6likuyphBV7SEtrqQrWKirUGrSoAGwphWRU1Kqqu8rSRwQokscipbrTkBUVdFpVTHR-hqx7tat0voFGwv6ZuVN0vpPxonTfO_Y81rM3ebJqcVKUmZCMiOQHkXgge9x1LSfEvR_EnRbKVIkIvDnXvA7-P5F3htjjc</recordid><startdate>20140730</startdate><enddate>20140730</enddate><creator>Kovacheva, Marineta</creator><creator>Zepp, Michael</creator><creator>Berger, Stefan M</creator><creator>Berger, Martin R</creator><general>Impact Journals LLC</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20140730</creationdate><title>Sustained conditional knockdown reveals intracellular bone sialoprotein as essential for breast cancer skeletal metastasis</title><author>Kovacheva, Marineta ; Zepp, Michael ; Berger, Stefan M ; Berger, Martin R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c396t-ed5b01bf5abc29b8efc79efe022fc58061f74b7ae3010a541abff30e98757ccd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Bone and Bones - metabolism</topic><topic>Bone and Bones - pathology</topic><topic>Bone Neoplasms - genetics</topic><topic>Bone Neoplasms - metabolism</topic><topic>Bone Neoplasms - secondary</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement - genetics</topic><topic>Clone Cells</topic><topic>Female</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene Knockdown Techniques</topic><topic>Humans</topic><topic>Male</topic><topic>Rats</topic><topic>Rats, Nude</topic><topic>Research Paper</topic><topic>Sialoglycoproteins - genetics</topic><topic>Sialoglycoproteins - metabolism</topic><topic>Transfection</topic><topic>Tumor Cells, Cultured</topic><toplevel>online_resources</toplevel><creatorcontrib>Kovacheva, Marineta</creatorcontrib><creatorcontrib>Zepp, Michael</creatorcontrib><creatorcontrib>Berger, Stefan M</creatorcontrib><creatorcontrib>Berger, Martin R</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kovacheva, Marineta</au><au>Zepp, Michael</au><au>Berger, Stefan M</au><au>Berger, Martin R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sustained conditional knockdown reveals intracellular bone sialoprotein as essential for breast cancer skeletal metastasis</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2014-07-30</date><risdate>2014</risdate><volume>5</volume><issue>14</issue><spage>5510</spage><epage>5522</epage><pages>5510-5522</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>Increased bone sialoprotein (BSP) serum levels are related to breast cancer skeletal metastasis, but their relevance is unknown. We elucidated novel intracellular BSP functions by a conditional knockdown of BSP. Conditional MDA-MB-231 subclones were equipped with a novel gene expression cassette containing a tet-reg-ulated miRNA providing knockdown of BSP production. These clones were used to assess the effect of BSP on morphology, proliferation, migration, colony formation and gene expression in vitro, and on soft tissue and osteolytic le-sions in a xenograft model by three imaging methods. BSP knockdown caused significant anti-proliferative, anti-migratory and anti-clonogenic effects in vitro (p<0.001). In vivo, significant de-creases of soft tissue and osteolytic lesions (p<0.03) were recorded after 3 weeks of miRNA treatment, leading to complete remission within 6 weeks. Microarray data revealed that 0.3% of genes were modulated in response to BSP knockdown. Upregulated genes included the endoplasmic reticulum stress genes ATF3 and DDIT3, the tumor suppressor gene EGR1, ID2 (related to breast epithelial differentiation), c-FOS and SERPINB2, whereas the metastasis associated genes CD44 and IL11 were downregulated. Also, activation of apoptotic pathways was demonstrated. These results implicate that intracellular BSP is essential for breast cancer skeletal metastasis and a target for treating these lesions.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>24980816</pmid><doi>10.18632/oncotarget.2132</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Bone and Bones - metabolism Bone and Bones - pathology Bone Neoplasms - genetics Bone Neoplasms - metabolism Bone Neoplasms - secondary Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Cell Line, Tumor Cell Movement - genetics Clone Cells Female Gene Expression Profiling Gene Expression Regulation, Neoplastic Gene Knockdown Techniques Humans Male Rats Rats, Nude Research Paper Sialoglycoproteins - genetics Sialoglycoproteins - metabolism Transfection Tumor Cells, Cultured |
| title | Sustained conditional knockdown reveals intracellular bone sialoprotein as essential for breast cancer skeletal metastasis |
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