Breast cancer tissue slices as a model for evaluation of response to rapamycin
Rapamycin is a selective inhibitor of the mammalian target of rapamycin (mTOR), a regulator kinase that integrates growth factors signaling via the phosphoinositide-3-kinase pathway and that has emerged as a novel therapeutic modality in breast cancer (BC). We propose a pre-clinical “ex-vivo” person...
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| Veröffentlicht in: | Cell and tissue research 2013-06, Vol.352 (3), p.671-684 |
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| creator | Grosso, Stana Helena Giorgi Katayama, Maria Lucia Hirata Roela, Rosimeire Aparecida Nonogaki, Suely Soares, Fernando Augusto Brentani, Helena Lima, Leandro Folgueira, Maria Aparecida Azevedo Koike Waitzberg, Angela Flávia Logullo Pasini, Fátima Solange Góes, João Carlos Guedes Sampaio Brentani, M. Mitzi |
| description | Rapamycin is a selective inhibitor of the mammalian target of rapamycin (mTOR), a regulator kinase that integrates growth factors signaling via the phosphoinositide-3-kinase pathway and that has emerged as a novel therapeutic modality in breast cancer (BC). We propose a pre-clinical “ex-vivo” personalized organotypic culture of BC that preserves the microenvironment to evaluate rapamycin-mediated gene expression changes. Freshly excised ductal invasive BC slices, 400 μm thick (n=30), were cultured in the presence or absence (control) of rapamycin (20 nM) for 24 h. Some slices were formalin-fixed for immunohistochemical determinations and some were processed for microarray analysis. Control slices in culture retained their tissue morphology and tissue viability (detected by BrdU uptake). The percentage of proliferating cells (assessed by Ki67) did not change up to 24 h of treatment. Immunohistochemical evaluation of p-AKT, p-mTOR, p-4EBP1 and p-S6K1 indicated that AKT/mTOR pathway activation was maintained during cultivation. For microarray analysis, slices were divided into two groups, according to the presence/absence of epidermal growth factor receptor-type 2 and analyzed separately. Limited overlap was seen among differentially expressed genes after treatment (P |
| doi_str_mv | 10.1007/s00441-013-1608-8 |
| format | Article |
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Mitzi</creator><creatorcontrib>Grosso, Stana Helena Giorgi ; Katayama, Maria Lucia Hirata ; Roela, Rosimeire Aparecida ; Nonogaki, Suely ; Soares, Fernando Augusto ; Brentani, Helena ; Lima, Leandro ; Folgueira, Maria Aparecida Azevedo Koike ; Waitzberg, Angela Flávia Logullo ; Pasini, Fátima Solange ; Góes, João Carlos Guedes Sampaio ; Brentani, M. Mitzi</creatorcontrib><description>Rapamycin is a selective inhibitor of the mammalian target of rapamycin (mTOR), a regulator kinase that integrates growth factors signaling via the phosphoinositide-3-kinase pathway and that has emerged as a novel therapeutic modality in breast cancer (BC). We propose a pre-clinical “ex-vivo” personalized organotypic culture of BC that preserves the microenvironment to evaluate rapamycin-mediated gene expression changes. Freshly excised ductal invasive BC slices, 400 μm thick (n=30), were cultured in the presence or absence (control) of rapamycin (20 nM) for 24 h. Some slices were formalin-fixed for immunohistochemical determinations and some were processed for microarray analysis. Control slices in culture retained their tissue morphology and tissue viability (detected by BrdU uptake). The percentage of proliferating cells (assessed by Ki67) did not change up to 24 h of treatment. Immunohistochemical evaluation of p-AKT, p-mTOR, p-4EBP1 and p-S6K1 indicated that AKT/mTOR pathway activation was maintained during cultivation. For microarray analysis, slices were divided into two groups, according to the presence/absence of epidermal growth factor receptor-type 2 and analyzed separately. Limited overlap was seen among differentially expressed genes after treatment (P<0.01) in both groups suggesting different responses to rapamycin between these BC subtypes. Ontology analysis indicated that genes involved in biosynthetic processes were commonly reduced by rapamycin. Our network analysis suggested that concerted expression of these genes might distinguish controls from treated slices. Thus, breast carcinoma slices constitute a suitable physiological tool to evaluate the short-term effects of rapamycin on the gene profile of individual BC samples.</description><identifier>ISSN: 0302-766X</identifier><identifier>EISSN: 1432-0878</identifier><identifier>DOI: 10.1007/s00441-013-1608-8</identifier><identifier>PMID: 23636418</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer-Verlag</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Analysis ; Biomedical and Life Sciences ; Biomedicine ; Breast cancer ; breast neoplasms ; Breast Neoplasms - drug therapy ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; carcinoma ; DNA microarrays ; epidermal growth factor ; Female ; Formaldehyde ; Gene expression ; Gene Expression Profiling ; gene expression regulation ; Gene Expression Regulation, Neoplastic - drug effects ; Gene Regulatory Networks - drug effects ; genes ; Human Genetics ; Humans ; Immunohistochemistry ; Inhibitor drugs ; Ki-67 Antigen - metabolism ; Kinases ; mammals ; microarray technology ; Middle Aged ; Models, Biological ; Molecular Medicine ; Neoplasm Proteins - genetics ; Neoplasm Proteins - metabolism ; Pharmacology ; Phosphoproteins - genetics ; Phosphoproteins - metabolism ; Proteomics ; Rapamycin ; Receptor, ErbB-2 - metabolism ; Regular Article ; Signal transduction ; Sirolimus - pharmacology ; Sirolimus - therapeutic use ; Tissue Culture Techniques ; viability</subject><ispartof>Cell and tissue research, 2013-06, Vol.352 (3), p.671-684</ispartof><rights>Springer-Verlag Berlin Heidelberg 2013</rights><rights>COPYRIGHT 2013 Springer</rights><rights>Springer-Verlag 2013</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c494t-5e58e49a2eacd989ec714f32aea3bbb3a5c44560e64407015bc4756cadcc61c83</citedby><cites>FETCH-LOGICAL-c494t-5e58e49a2eacd989ec714f32aea3bbb3a5c44560e64407015bc4756cadcc61c83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00441-013-1608-8$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00441-013-1608-8$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>315,782,786,27931,27932,41495,42564,51326</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23636418$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Grosso, Stana Helena Giorgi</creatorcontrib><creatorcontrib>Katayama, Maria Lucia Hirata</creatorcontrib><creatorcontrib>Roela, Rosimeire Aparecida</creatorcontrib><creatorcontrib>Nonogaki, Suely</creatorcontrib><creatorcontrib>Soares, Fernando Augusto</creatorcontrib><creatorcontrib>Brentani, Helena</creatorcontrib><creatorcontrib>Lima, Leandro</creatorcontrib><creatorcontrib>Folgueira, Maria Aparecida Azevedo Koike</creatorcontrib><creatorcontrib>Waitzberg, Angela Flávia Logullo</creatorcontrib><creatorcontrib>Pasini, Fátima Solange</creatorcontrib><creatorcontrib>Góes, João Carlos Guedes Sampaio</creatorcontrib><creatorcontrib>Brentani, M. Mitzi</creatorcontrib><title>Breast cancer tissue slices as a model for evaluation of response to rapamycin</title><title>Cell and tissue research</title><addtitle>Cell Tissue Res</addtitle><addtitle>Cell Tissue Res</addtitle><description>Rapamycin is a selective inhibitor of the mammalian target of rapamycin (mTOR), a regulator kinase that integrates growth factors signaling via the phosphoinositide-3-kinase pathway and that has emerged as a novel therapeutic modality in breast cancer (BC). We propose a pre-clinical “ex-vivo” personalized organotypic culture of BC that preserves the microenvironment to evaluate rapamycin-mediated gene expression changes. Freshly excised ductal invasive BC slices, 400 μm thick (n=30), were cultured in the presence or absence (control) of rapamycin (20 nM) for 24 h. Some slices were formalin-fixed for immunohistochemical determinations and some were processed for microarray analysis. Control slices in culture retained their tissue morphology and tissue viability (detected by BrdU uptake). The percentage of proliferating cells (assessed by Ki67) did not change up to 24 h of treatment. Immunohistochemical evaluation of p-AKT, p-mTOR, p-4EBP1 and p-S6K1 indicated that AKT/mTOR pathway activation was maintained during cultivation. For microarray analysis, slices were divided into two groups, according to the presence/absence of epidermal growth factor receptor-type 2 and analyzed separately. Limited overlap was seen among differentially expressed genes after treatment (P<0.01) in both groups suggesting different responses to rapamycin between these BC subtypes. Ontology analysis indicated that genes involved in biosynthetic processes were commonly reduced by rapamycin. Our network analysis suggested that concerted expression of these genes might distinguish controls from treated slices. Thus, breast carcinoma slices constitute a suitable physiological tool to evaluate the short-term effects of rapamycin on the gene profile of individual BC samples.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Analysis</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Breast cancer</subject><subject>breast neoplasms</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>carcinoma</subject><subject>DNA microarrays</subject><subject>epidermal growth factor</subject><subject>Female</subject><subject>Formaldehyde</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>gene expression regulation</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Gene Regulatory Networks - drug effects</subject><subject>genes</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Inhibitor drugs</subject><subject>Ki-67 Antigen - metabolism</subject><subject>Kinases</subject><subject>mammals</subject><subject>microarray technology</subject><subject>Middle Aged</subject><subject>Models, Biological</subject><subject>Molecular Medicine</subject><subject>Neoplasm Proteins - genetics</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Pharmacology</subject><subject>Phosphoproteins - genetics</subject><subject>Phosphoproteins - metabolism</subject><subject>Proteomics</subject><subject>Rapamycin</subject><subject>Receptor, ErbB-2 - metabolism</subject><subject>Regular Article</subject><subject>Signal transduction</subject><subject>Sirolimus - pharmacology</subject><subject>Sirolimus - therapeutic use</subject><subject>Tissue Culture Techniques</subject><subject>viability</subject><issn>0302-766X</issn><issn>1432-0878</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kt1r1jAUxoMo7nX6B3ijAUG86cxX0_RyDr9g6IUOvAun6em7jrZ5zWmF_femdOomIgkEkt_zkHOew9hTKU6kENVrEsIYWQipC2mFK9w9tpNGq0K4yt1nO6GFKiprvx2xR0RXQkhjbf2QHSlttTXS7dinNwmBZh5gCpj43BMtyGnoAxKHvPkYWxx4FxPHHzAsMPdx4rHjCekQJ0I-R57gAON16KfH7EEHA-GTm_OYXbx7-_XsQ3H--f3Hs9PzIpjazEWJpUNTg0IIbe1qDJU0nVaAoJum0VAGY0or0BojKiHLJpiqtAHaEKwMTh-zV5vvIcXvC9Lsx54CDgNMGBfyUpdWO6eVyeiLv9CruKQp_26lSmWcU_Ufag8D-n7q4pwgrKb-VOtaSCekzNTJP6i8Whz7ECfs-nx_R_DyluASYZgvKQ7L2kS6C8oNDCkSJez8IfUjpGsvhV_D9lvYPoft17D92oRnN5UtzYjtb8WvdDOgNoDy07THdKv0_7g-30QdRA_71JO_-KLy6OTx0dq4Wv8E2WK6QQ</recordid><startdate>20130601</startdate><enddate>20130601</enddate><creator>Grosso, Stana Helena Giorgi</creator><creator>Katayama, Maria Lucia Hirata</creator><creator>Roela, Rosimeire Aparecida</creator><creator>Nonogaki, Suely</creator><creator>Soares, Fernando Augusto</creator><creator>Brentani, Helena</creator><creator>Lima, Leandro</creator><creator>Folgueira, Maria Aparecida Azevedo Koike</creator><creator>Waitzberg, Angela Flávia Logullo</creator><creator>Pasini, Fátima Solange</creator><creator>Góes, João Carlos Guedes Sampaio</creator><creator>Brentani, M. 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Mitzi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c494t-5e58e49a2eacd989ec714f32aea3bbb3a5c44560e64407015bc4756cadcc61c83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Analysis</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Breast cancer</topic><topic>breast neoplasms</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>carcinoma</topic><topic>DNA microarrays</topic><topic>epidermal growth factor</topic><topic>Female</topic><topic>Formaldehyde</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>gene expression regulation</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Gene Regulatory Networks - drug effects</topic><topic>genes</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Inhibitor drugs</topic><topic>Ki-67 Antigen - metabolism</topic><topic>Kinases</topic><topic>mammals</topic><topic>microarray technology</topic><topic>Middle Aged</topic><topic>Models, Biological</topic><topic>Molecular Medicine</topic><topic>Neoplasm Proteins - genetics</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Pharmacology</topic><topic>Phosphoproteins - genetics</topic><topic>Phosphoproteins - metabolism</topic><topic>Proteomics</topic><topic>Rapamycin</topic><topic>Receptor, ErbB-2 - metabolism</topic><topic>Regular Article</topic><topic>Signal transduction</topic><topic>Sirolimus - pharmacology</topic><topic>Sirolimus - therapeutic use</topic><topic>Tissue Culture Techniques</topic><topic>viability</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Grosso, Stana Helena Giorgi</creatorcontrib><creatorcontrib>Katayama, Maria Lucia Hirata</creatorcontrib><creatorcontrib>Roela, Rosimeire Aparecida</creatorcontrib><creatorcontrib>Nonogaki, Suely</creatorcontrib><creatorcontrib>Soares, Fernando Augusto</creatorcontrib><creatorcontrib>Brentani, Helena</creatorcontrib><creatorcontrib>Lima, Leandro</creatorcontrib><creatorcontrib>Folgueira, Maria Aparecida Azevedo Koike</creatorcontrib><creatorcontrib>Waitzberg, Angela Flávia Logullo</creatorcontrib><creatorcontrib>Pasini, Fátima Solange</creatorcontrib><creatorcontrib>Góes, João Carlos Guedes Sampaio</creatorcontrib><creatorcontrib>Brentani, M. 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Mitzi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Breast cancer tissue slices as a model for evaluation of response to rapamycin</atitle><jtitle>Cell and tissue research</jtitle><stitle>Cell Tissue Res</stitle><addtitle>Cell Tissue Res</addtitle><date>2013-06-01</date><risdate>2013</risdate><volume>352</volume><issue>3</issue><spage>671</spage><epage>684</epage><pages>671-684</pages><issn>0302-766X</issn><eissn>1432-0878</eissn><abstract>Rapamycin is a selective inhibitor of the mammalian target of rapamycin (mTOR), a regulator kinase that integrates growth factors signaling via the phosphoinositide-3-kinase pathway and that has emerged as a novel therapeutic modality in breast cancer (BC). We propose a pre-clinical “ex-vivo” personalized organotypic culture of BC that preserves the microenvironment to evaluate rapamycin-mediated gene expression changes. Freshly excised ductal invasive BC slices, 400 μm thick (n=30), were cultured in the presence or absence (control) of rapamycin (20 nM) for 24 h. Some slices were formalin-fixed for immunohistochemical determinations and some were processed for microarray analysis. Control slices in culture retained their tissue morphology and tissue viability (detected by BrdU uptake). The percentage of proliferating cells (assessed by Ki67) did not change up to 24 h of treatment. Immunohistochemical evaluation of p-AKT, p-mTOR, p-4EBP1 and p-S6K1 indicated that AKT/mTOR pathway activation was maintained during cultivation. For microarray analysis, slices were divided into two groups, according to the presence/absence of epidermal growth factor receptor-type 2 and analyzed separately. Limited overlap was seen among differentially expressed genes after treatment (P<0.01) in both groups suggesting different responses to rapamycin between these BC subtypes. Ontology analysis indicated that genes involved in biosynthetic processes were commonly reduced by rapamycin. Our network analysis suggested that concerted expression of these genes might distinguish controls from treated slices. Thus, breast carcinoma slices constitute a suitable physiological tool to evaluate the short-term effects of rapamycin on the gene profile of individual BC samples.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer-Verlag</pub><pmid>23636418</pmid><doi>10.1007/s00441-013-1608-8</doi><tpages>14</tpages></addata></record> |
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| subjects | Adult Aged Aged, 80 and over Analysis Biomedical and Life Sciences Biomedicine Breast cancer breast neoplasms Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology carcinoma DNA microarrays epidermal growth factor Female Formaldehyde Gene expression Gene Expression Profiling gene expression regulation Gene Expression Regulation, Neoplastic - drug effects Gene Regulatory Networks - drug effects genes Human Genetics Humans Immunohistochemistry Inhibitor drugs Ki-67 Antigen - metabolism Kinases mammals microarray technology Middle Aged Models, Biological Molecular Medicine Neoplasm Proteins - genetics Neoplasm Proteins - metabolism Pharmacology Phosphoproteins - genetics Phosphoproteins - metabolism Proteomics Rapamycin Receptor, ErbB-2 - metabolism Regular Article Signal transduction Sirolimus - pharmacology Sirolimus - therapeutic use Tissue Culture Techniques viability |
| title | Breast cancer tissue slices as a model for evaluation of response to rapamycin |
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