CDC42 as an epigenetic regulator of ID4 in triple-negative breast tumors
Background Triple-negative (TN) breast cancer represents a subtype of breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER-2). Clinically, it is characterized by high invasiveness, high metastatic potential, and poor...
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| Veröffentlicht in: | Breast cancer (Tokyo, Japan) Japan), 2022-05, Vol.29 (3), p.562-573 |
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| creator | Nasif, Daniela Real, Sebastian Roqué, María Branham, María T. |
| description | Background
Triple-negative (TN) breast cancer represents a subtype of breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER-2). Clinically, it is characterized by high invasiveness, high metastatic potential, and poor prognosis. Inhibitor of DNA binding 4 (ID4) has been shown to be overexpressed in these tumors acting as an oncogene responsible for many of its aggressive features. CDC42, a plasma membrane-associated small GTPase, can downregulate ID4 gene expression through hypermethylation of its promoter in colorectal adenocarcinomas. Since ID4 acts as an oncogene and is hypomethylated in TN breast tumors, here we asked whether CDC42 could also epigenetically silence ID4 and in doing so revert aggressive features of this tumor type.
Methods
Gene expression was retrieved from TCGA database using UCSC Xena. Association between overall survival (OS) and gene expression was assessed using Kaplan–Meier plotter. In vitro experiments involved ectopic expression of CDC42 in MDA-MB231and in MDA-MB468 breast cancer cell lines. Gene expression was analyzed by qPCR, western blot and inmunofluorescence assays and methylation by MSP, MS-MLPA, or ddMSP.
Results
Data mining analysis revealed that CDC42 expression varies among breast cancer subtypes that in the basal-like subtype there is an inverse correlation between CDC42 and ID4 expression and a positive correlation between CDC42 expression and ID4 methylation. In vitro experiments revealed that CDC42 overexpression induced ID4 methylation through the activation of the EZH2 pathway. ID4 silencing produced an increase in BRCA1 expression and a less aggressive phenotype in the tested cell line.
Conclusion
We show that CDC42 silences ID4 through methylation in TN breast cancer. Given that ID4 acts as an oncogene in these tumors, we think that finding an epigenetic regulator of ID4 contributes to the research and clinical management of TN breast tumors. |
| doi_str_mv | 10.1007/s12282-022-01334-4 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_proquest_miscellaneous_2624199280</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A706381815</galeid><sourcerecordid>A706381815</sourcerecordid><originalsourceid>FETCH-LOGICAL-c438t-c9b429c9a65e02a2bac31a578367beeadaff401811d3adccb313d984c91d85fd3</originalsourceid><addsrcrecordid>eNp9kUFrFjEQhoMotlb_gAcJePGyNclk98sey1e1hYIXPYfZ7OySspt8JlnBf2_qVkEQCSHD5HlnhnkZey3FpRTi8D5LpYxqhKpXAuhGP2Hn0hjRaAXwtMagRdOZzpyxFznfC6HhILrn7Axa0WvVwzm7OV4fteKYOQZOJz9ToOIdTzRvC5aYeJz47bXmPvCS_GmhJtCMxX8nPiTCXHjZ1pjyS_ZswiXTq8f3gn39-OHL8aa5-_zp9nh11zgNpjSuH2pj12PXklCoBnQgsT0Y6A4DEY44TVpII-UIODo3gISxN9r1cjTtNMIFe7fXPaX4baNc7Oqzo2XBQHHLVnVKy75XRlT07Y7OuJD1YYoloXvA7VXdA5japq3U5T-oekZavYuBJl_zfwnULnAp5pxosqfkV0w_rBT2wRi7G2OrMfaXMVZX0ZvHsbdhpfGP5LcTFYAdyPUrzJTsfdxSqKv8X9mffzGWJw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2624199280</pqid></control><display><type>article</type><title>CDC42 as an epigenetic regulator of ID4 in triple-negative breast tumors</title><source>MEDLINE</source><source>SpringerLink Journals</source><creator>Nasif, Daniela ; Real, Sebastian ; Roqué, María ; Branham, María T.</creator><creatorcontrib>Nasif, Daniela ; Real, Sebastian ; Roqué, María ; Branham, María T.</creatorcontrib><description>Background
Triple-negative (TN) breast cancer represents a subtype of breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER-2). Clinically, it is characterized by high invasiveness, high metastatic potential, and poor prognosis. Inhibitor of DNA binding 4 (ID4) has been shown to be overexpressed in these tumors acting as an oncogene responsible for many of its aggressive features. CDC42, a plasma membrane-associated small GTPase, can downregulate ID4 gene expression through hypermethylation of its promoter in colorectal adenocarcinomas. Since ID4 acts as an oncogene and is hypomethylated in TN breast tumors, here we asked whether CDC42 could also epigenetically silence ID4 and in doing so revert aggressive features of this tumor type.
Methods
Gene expression was retrieved from TCGA database using UCSC Xena. Association between overall survival (OS) and gene expression was assessed using Kaplan–Meier plotter. In vitro experiments involved ectopic expression of CDC42 in MDA-MB231and in MDA-MB468 breast cancer cell lines. Gene expression was analyzed by qPCR, western blot and inmunofluorescence assays and methylation by MSP, MS-MLPA, or ddMSP.
Results
Data mining analysis revealed that CDC42 expression varies among breast cancer subtypes that in the basal-like subtype there is an inverse correlation between CDC42 and ID4 expression and a positive correlation between CDC42 expression and ID4 methylation. In vitro experiments revealed that CDC42 overexpression induced ID4 methylation through the activation of the EZH2 pathway. ID4 silencing produced an increase in BRCA1 expression and a less aggressive phenotype in the tested cell line.
Conclusion
We show that CDC42 silences ID4 through methylation in TN breast cancer. Given that ID4 acts as an oncogene in these tumors, we think that finding an epigenetic regulator of ID4 contributes to the research and clinical management of TN breast tumors.</description><identifier>ISSN: 1340-6868</identifier><identifier>EISSN: 1880-4233</identifier><identifier>DOI: 10.1007/s12282-022-01334-4</identifier><identifier>PMID: 35094293</identifier><language>eng</language><publisher>Singapore: Springer Nature Singapore</publisher><subject>Analysis ; Breast cancer ; Breast Neoplasms - pathology ; Cancer Research ; cdc42 GTP-Binding Protein ; Colorectal cancer ; Development and progression ; DNA Methylation ; Epidermal growth factor ; Epigenesis, Genetic ; Epigenetic inheritance ; Estrogen ; Female ; Gene expression ; Gene Expression Regulation, Neoplastic ; Genes ; Genetic aspects ; Humans ; Inhibitor of Differentiation Proteins - genetics ; Inhibitor of Differentiation Proteins - metabolism ; Medicine ; Medicine & Public Health ; Metastasis ; Methylation ; Oncology ; Original Article ; Progesterone ; Prognosis ; Promoter Regions, Genetic ; Receptors, Estrogen - metabolism ; Surgery ; Surgical Oncology ; Triple Negative Breast Neoplasms - genetics ; Triple Negative Breast Neoplasms - pathology</subject><ispartof>Breast cancer (Tokyo, Japan), 2022-05, Vol.29 (3), p.562-573</ispartof><rights>The Author(s), under exclusive licence to The Japanese Breast Cancer Society 2022</rights><rights>2022. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.</rights><rights>COPYRIGHT 2022 Springer</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c438t-c9b429c9a65e02a2bac31a578367beeadaff401811d3adccb313d984c91d85fd3</citedby><cites>FETCH-LOGICAL-c438t-c9b429c9a65e02a2bac31a578367beeadaff401811d3adccb313d984c91d85fd3</cites><orcidid>0000-0003-0362-0240</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s12282-022-01334-4$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s12282-022-01334-4$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35094293$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nasif, Daniela</creatorcontrib><creatorcontrib>Real, Sebastian</creatorcontrib><creatorcontrib>Roqué, María</creatorcontrib><creatorcontrib>Branham, María T.</creatorcontrib><title>CDC42 as an epigenetic regulator of ID4 in triple-negative breast tumors</title><title>Breast cancer (Tokyo, Japan)</title><addtitle>Breast Cancer</addtitle><addtitle>Breast Cancer</addtitle><description>Background
Triple-negative (TN) breast cancer represents a subtype of breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER-2). Clinically, it is characterized by high invasiveness, high metastatic potential, and poor prognosis. Inhibitor of DNA binding 4 (ID4) has been shown to be overexpressed in these tumors acting as an oncogene responsible for many of its aggressive features. CDC42, a plasma membrane-associated small GTPase, can downregulate ID4 gene expression through hypermethylation of its promoter in colorectal adenocarcinomas. Since ID4 acts as an oncogene and is hypomethylated in TN breast tumors, here we asked whether CDC42 could also epigenetically silence ID4 and in doing so revert aggressive features of this tumor type.
Methods
Gene expression was retrieved from TCGA database using UCSC Xena. Association between overall survival (OS) and gene expression was assessed using Kaplan–Meier plotter. In vitro experiments involved ectopic expression of CDC42 in MDA-MB231and in MDA-MB468 breast cancer cell lines. Gene expression was analyzed by qPCR, western blot and inmunofluorescence assays and methylation by MSP, MS-MLPA, or ddMSP.
Results
Data mining analysis revealed that CDC42 expression varies among breast cancer subtypes that in the basal-like subtype there is an inverse correlation between CDC42 and ID4 expression and a positive correlation between CDC42 expression and ID4 methylation. In vitro experiments revealed that CDC42 overexpression induced ID4 methylation through the activation of the EZH2 pathway. ID4 silencing produced an increase in BRCA1 expression and a less aggressive phenotype in the tested cell line.
Conclusion
We show that CDC42 silences ID4 through methylation in TN breast cancer. Given that ID4 acts as an oncogene in these tumors, we think that finding an epigenetic regulator of ID4 contributes to the research and clinical management of TN breast tumors.</description><subject>Analysis</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - pathology</subject><subject>Cancer Research</subject><subject>cdc42 GTP-Binding Protein</subject><subject>Colorectal cancer</subject><subject>Development and progression</subject><subject>DNA Methylation</subject><subject>Epidermal growth factor</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetic inheritance</subject><subject>Estrogen</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Humans</subject><subject>Inhibitor of Differentiation Proteins - genetics</subject><subject>Inhibitor of Differentiation Proteins - metabolism</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metastasis</subject><subject>Methylation</subject><subject>Oncology</subject><subject>Original Article</subject><subject>Progesterone</subject><subject>Prognosis</subject><subject>Promoter Regions, Genetic</subject><subject>Receptors, Estrogen - metabolism</subject><subject>Surgery</subject><subject>Surgical Oncology</subject><subject>Triple Negative Breast Neoplasms - genetics</subject><subject>Triple Negative Breast Neoplasms - pathology</subject><issn>1340-6868</issn><issn>1880-4233</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUFrFjEQhoMotlb_gAcJePGyNclk98sey1e1hYIXPYfZ7OySspt8JlnBf2_qVkEQCSHD5HlnhnkZey3FpRTi8D5LpYxqhKpXAuhGP2Hn0hjRaAXwtMagRdOZzpyxFznfC6HhILrn7Axa0WvVwzm7OV4fteKYOQZOJz9ToOIdTzRvC5aYeJz47bXmPvCS_GmhJtCMxX8nPiTCXHjZ1pjyS_ZswiXTq8f3gn39-OHL8aa5-_zp9nh11zgNpjSuH2pj12PXklCoBnQgsT0Y6A4DEY44TVpII-UIODo3gISxN9r1cjTtNMIFe7fXPaX4baNc7Oqzo2XBQHHLVnVKy75XRlT07Y7OuJD1YYoloXvA7VXdA5japq3U5T-oekZavYuBJl_zfwnULnAp5pxosqfkV0w_rBT2wRi7G2OrMfaXMVZX0ZvHsbdhpfGP5LcTFYAdyPUrzJTsfdxSqKv8X9mffzGWJw</recordid><startdate>20220501</startdate><enddate>20220501</enddate><creator>Nasif, Daniela</creator><creator>Real, Sebastian</creator><creator>Roqué, María</creator><creator>Branham, María T.</creator><general>Springer Nature Singapore</general><general>Springer</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>7X8</scope><orcidid>https://orcid.org/0000-0003-0362-0240</orcidid></search><sort><creationdate>20220501</creationdate><title>CDC42 as an epigenetic regulator of ID4 in triple-negative breast tumors</title><author>Nasif, Daniela ; Real, Sebastian ; Roqué, María ; Branham, María T.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c438t-c9b429c9a65e02a2bac31a578367beeadaff401811d3adccb313d984c91d85fd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Analysis</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - pathology</topic><topic>Cancer Research</topic><topic>cdc42 GTP-Binding Protein</topic><topic>Colorectal cancer</topic><topic>Development and progression</topic><topic>DNA Methylation</topic><topic>Epidermal growth factor</topic><topic>Epigenesis, Genetic</topic><topic>Epigenetic inheritance</topic><topic>Estrogen</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Humans</topic><topic>Inhibitor of Differentiation Proteins - genetics</topic><topic>Inhibitor of Differentiation Proteins - metabolism</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metastasis</topic><topic>Methylation</topic><topic>Oncology</topic><topic>Original Article</topic><topic>Progesterone</topic><topic>Prognosis</topic><topic>Promoter Regions, Genetic</topic><topic>Receptors, Estrogen - metabolism</topic><topic>Surgery</topic><topic>Surgical Oncology</topic><topic>Triple Negative Breast Neoplasms - genetics</topic><topic>Triple Negative Breast Neoplasms - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nasif, Daniela</creatorcontrib><creatorcontrib>Real, Sebastian</creatorcontrib><creatorcontrib>Roqué, María</creatorcontrib><creatorcontrib>Branham, María T.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Breast cancer (Tokyo, Japan)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nasif, Daniela</au><au>Real, Sebastian</au><au>Roqué, María</au><au>Branham, María T.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CDC42 as an epigenetic regulator of ID4 in triple-negative breast tumors</atitle><jtitle>Breast cancer (Tokyo, Japan)</jtitle><stitle>Breast Cancer</stitle><addtitle>Breast Cancer</addtitle><date>2022-05-01</date><risdate>2022</risdate><volume>29</volume><issue>3</issue><spage>562</spage><epage>573</epage><pages>562-573</pages><issn>1340-6868</issn><eissn>1880-4233</eissn><abstract>Background
Triple-negative (TN) breast cancer represents a subtype of breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER-2). Clinically, it is characterized by high invasiveness, high metastatic potential, and poor prognosis. Inhibitor of DNA binding 4 (ID4) has been shown to be overexpressed in these tumors acting as an oncogene responsible for many of its aggressive features. CDC42, a plasma membrane-associated small GTPase, can downregulate ID4 gene expression through hypermethylation of its promoter in colorectal adenocarcinomas. Since ID4 acts as an oncogene and is hypomethylated in TN breast tumors, here we asked whether CDC42 could also epigenetically silence ID4 and in doing so revert aggressive features of this tumor type.
Methods
Gene expression was retrieved from TCGA database using UCSC Xena. Association between overall survival (OS) and gene expression was assessed using Kaplan–Meier plotter. In vitro experiments involved ectopic expression of CDC42 in MDA-MB231and in MDA-MB468 breast cancer cell lines. Gene expression was analyzed by qPCR, western blot and inmunofluorescence assays and methylation by MSP, MS-MLPA, or ddMSP.
Results
Data mining analysis revealed that CDC42 expression varies among breast cancer subtypes that in the basal-like subtype there is an inverse correlation between CDC42 and ID4 expression and a positive correlation between CDC42 expression and ID4 methylation. In vitro experiments revealed that CDC42 overexpression induced ID4 methylation through the activation of the EZH2 pathway. ID4 silencing produced an increase in BRCA1 expression and a less aggressive phenotype in the tested cell line.
Conclusion
We show that CDC42 silences ID4 through methylation in TN breast cancer. Given that ID4 acts as an oncogene in these tumors, we think that finding an epigenetic regulator of ID4 contributes to the research and clinical management of TN breast tumors.</abstract><cop>Singapore</cop><pub>Springer Nature Singapore</pub><pmid>35094293</pmid><doi>10.1007/s12282-022-01334-4</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-0362-0240</orcidid></addata></record> |
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| subjects | Analysis Breast cancer Breast Neoplasms - pathology Cancer Research cdc42 GTP-Binding Protein Colorectal cancer Development and progression DNA Methylation Epidermal growth factor Epigenesis, Genetic Epigenetic inheritance Estrogen Female Gene expression Gene Expression Regulation, Neoplastic Genes Genetic aspects Humans Inhibitor of Differentiation Proteins - genetics Inhibitor of Differentiation Proteins - metabolism Medicine Medicine & Public Health Metastasis Methylation Oncology Original Article Progesterone Prognosis Promoter Regions, Genetic Receptors, Estrogen - metabolism Surgery Surgical Oncology Triple Negative Breast Neoplasms - genetics Triple Negative Breast Neoplasms - pathology |
| title | CDC42 as an epigenetic regulator of ID4 in triple-negative breast tumors |
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