Gadd45a Functions as a Promoter or Suppressor of Breast Cancer Dependent on the Oncogenic Stress
Gadd45a plays a pivotal role as a stress sensor that modulates cellular responses to various stress stimuli including oncogenic stress. We reported that the stress sensor Gadd45a gene functions as a tumor suppressor in Ras-driven breast tumorigenesis via increasing JNK-mediated apoptosis and p38-med...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2010-12, Vol.70 (23), p.9671-9681 |
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| creator | TRONT, Jennifer S YAJUE HUANG FORNACE, Albert A HOFFMAN, Barbara LIEBERMANN, Dan A |
| description | Gadd45a plays a pivotal role as a stress sensor that modulates cellular responses to various stress stimuli including oncogenic stress. We reported that the stress sensor Gadd45a gene functions as a tumor suppressor in Ras-driven breast tumorigenesis via increasing JNK-mediated apoptosis and p38-mediated senescence. In contrast, here, we show that Gadd45a promotes Myc-driven breast cancer by negatively regulating MMP10 via GSK3 β/β-catenin signaling, resulting in increased tumor vascularization and growth. These novel findings indicate that Gadd45a functions as either tumor promoter or suppressor, is dependent on the oncogenic stress, and is mediated via distinct signaling pathways. Collectively, these novel findings highlight the significance of the type of oncogenic alteration on how stress response genes function during initiation and progression of tumorigenesis. Because Gadd45a is a target for BRCA1 and p53, these findings have implications regarding BRCA1/p53 tumor suppressor functions. |
| doi_str_mv | 10.1158/0008-5472.can-10-2177 |
| format | Article |
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We reported that the stress sensor Gadd45a gene functions as a tumor suppressor in Ras-driven breast tumorigenesis via increasing JNK-mediated apoptosis and p38-mediated senescence. In contrast, here, we show that Gadd45a promotes Myc-driven breast cancer by negatively regulating MMP10 via GSK3 β/β-catenin signaling, resulting in increased tumor vascularization and growth. These novel findings indicate that Gadd45a functions as either tumor promoter or suppressor, is dependent on the oncogenic stress, and is mediated via distinct signaling pathways. Collectively, these novel findings highlight the significance of the type of oncogenic alteration on how stress response genes function during initiation and progression of tumorigenesis. Because Gadd45a is a target for BRCA1 and p53, these findings have implications regarding BRCA1/p53 tumor suppressor functions.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.can-10-2177</identifier><identifier>PMID: 21098706</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Animals ; Antineoplastic agents ; beta Catenin - metabolism ; Biological and medical sciences ; Blotting, Western ; Cell Cycle Proteins - genetics ; Cell Cycle Proteins - metabolism ; Cell Cycle Proteins - physiology ; Female ; Gene Expression Regulation, Neoplastic ; Genes, myc - genetics ; Genes, myc - physiology ; Glycogen Synthase Kinase 3 - metabolism ; Glycogen Synthase Kinase 3 beta ; Gynecology. Andrology. Obstetrics ; Immunohistochemistry ; Male ; Mammary gland diseases ; Mammary Neoplasms, Animal - genetics ; Mammary Neoplasms, Animal - metabolism ; Mammary Neoplasms, Animal - pathology ; Matrix Metalloproteinase 10 - genetics ; Matrix Metalloproteinase 10 - metabolism ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Neovascularization, Pathologic - pathology ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Nuclear Proteins - physiology ; Pharmacology. Drug treatments ; RNA Interference ; Signal Transduction ; Tumor Burden ; Tumor Suppressor Proteins - genetics ; Tumor Suppressor Proteins - metabolism ; Tumor Suppressor Proteins - physiology ; Tumors</subject><ispartof>Cancer research (Chicago, Ill.), 2010-12, Vol.70 (23), p.9671-9681</ispartof><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c538t-2cdc9ed28d33f4a0e718c91fcdcd15e8e3fd5e209f55fe1d80caec40f874d7a93</citedby><cites>FETCH-LOGICAL-c538t-2cdc9ed28d33f4a0e718c91fcdcd15e8e3fd5e209f55fe1d80caec40f874d7a93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3342,27903,27904</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23620061$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21098706$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>TRONT, Jennifer S</creatorcontrib><creatorcontrib>YAJUE HUANG</creatorcontrib><creatorcontrib>FORNACE, Albert A</creatorcontrib><creatorcontrib>HOFFMAN, Barbara</creatorcontrib><creatorcontrib>LIEBERMANN, Dan A</creatorcontrib><title>Gadd45a Functions as a Promoter or Suppressor of Breast Cancer Dependent on the Oncogenic Stress</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Gadd45a plays a pivotal role as a stress sensor that modulates cellular responses to various stress stimuli including oncogenic stress. We reported that the stress sensor Gadd45a gene functions as a tumor suppressor in Ras-driven breast tumorigenesis via increasing JNK-mediated apoptosis and p38-mediated senescence. In contrast, here, we show that Gadd45a promotes Myc-driven breast cancer by negatively regulating MMP10 via GSK3 β/β-catenin signaling, resulting in increased tumor vascularization and growth. These novel findings indicate that Gadd45a functions as either tumor promoter or suppressor, is dependent on the oncogenic stress, and is mediated via distinct signaling pathways. Collectively, these novel findings highlight the significance of the type of oncogenic alteration on how stress response genes function during initiation and progression of tumorigenesis. Because Gadd45a is a target for BRCA1 and p53, these findings have implications regarding BRCA1/p53 tumor suppressor functions.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>beta Catenin - metabolism</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Cell Cycle Proteins - physiology</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genes, myc - genetics</subject><subject>Genes, myc - physiology</subject><subject>Glycogen Synthase Kinase 3 - metabolism</subject><subject>Glycogen Synthase Kinase 3 beta</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Immunohistochemistry</subject><subject>Male</subject><subject>Mammary gland diseases</subject><subject>Mammary Neoplasms, Animal - genetics</subject><subject>Mammary Neoplasms, Animal - metabolism</subject><subject>Mammary Neoplasms, Animal - pathology</subject><subject>Matrix Metalloproteinase 10 - genetics</subject><subject>Matrix Metalloproteinase 10 - metabolism</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mice, Transgenic</subject><subject>Neovascularization, Pathologic - pathology</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>Nuclear Proteins - physiology</subject><subject>Pharmacology. Drug treatments</subject><subject>RNA Interference</subject><subject>Signal Transduction</subject><subject>Tumor Burden</subject><subject>Tumor Suppressor Proteins - genetics</subject><subject>Tumor Suppressor Proteins - metabolism</subject><subject>Tumor Suppressor Proteins - physiology</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkVFrFTEQhYMo9rb6E5S8iE9bM9nNJnkR6tW2QrFC9TnGZNKu7E3WZFfw35ul16s-CYFkZr5zmHAIeQbsFECoV4wx1YhO8lNnYwOs4SDlA7IB0apGdp14SDYH5ogcl_KtlgKYeEyOODCtJOs35MuF9b4Tlp4v0c1DioXaeujHnHZpxkxTpjfLNGUspT5ToG8y2jLTrY2ujt_ihNFjnGmKdL5Deh1dusU4OHozr6In5FGwY8Gn-_uEfD5_92l72VxdX7zfnl01ri48N9x5p9Fz5ds2dJahBOU0hNr2IFBhG7xAznQQIiB4xZxF17GgZOel1e0JeX3vOy1fd-hdXSnb0Ux52Nn80yQ7mH8ncbgzt-mHaUFr6Hg1eLk3yOn7gmU2u6E4HEcbMS3FaCah0z3v_0sq6KXmTK2e4p50OZWSMRz2AWbWGM0akVkjMtuzD2t3jbHqnv_9mYPqd24VeLEHbHF2DLmmMZQ_XNtzxnpofwEtlqfN</recordid><startdate>20101201</startdate><enddate>20101201</enddate><creator>TRONT, Jennifer S</creator><creator>YAJUE HUANG</creator><creator>FORNACE, Albert A</creator><creator>HOFFMAN, Barbara</creator><creator>LIEBERMANN, Dan A</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><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><scope>7TO</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20101201</creationdate><title>Gadd45a Functions as a Promoter or Suppressor of Breast Cancer Dependent on the Oncogenic Stress</title><author>TRONT, Jennifer S ; YAJUE HUANG ; FORNACE, Albert A ; HOFFMAN, Barbara ; LIEBERMANN, Dan A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c538t-2cdc9ed28d33f4a0e718c91fcdcd15e8e3fd5e209f55fe1d80caec40f874d7a93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>beta Catenin - metabolism</topic><topic>Biological and medical sciences</topic><topic>Blotting, Western</topic><topic>Cell Cycle Proteins - genetics</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Cell Cycle Proteins - physiology</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genes, myc - genetics</topic><topic>Genes, myc - physiology</topic><topic>Glycogen Synthase Kinase 3 - metabolism</topic><topic>Glycogen Synthase Kinase 3 beta</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Immunohistochemistry</topic><topic>Male</topic><topic>Mammary gland diseases</topic><topic>Mammary Neoplasms, Animal - genetics</topic><topic>Mammary Neoplasms, Animal - metabolism</topic><topic>Mammary Neoplasms, Animal - pathology</topic><topic>Matrix Metalloproteinase 10 - genetics</topic><topic>Matrix Metalloproteinase 10 - metabolism</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mice, Transgenic</topic><topic>Neovascularization, Pathologic - pathology</topic><topic>Nuclear Proteins - genetics</topic><topic>Nuclear Proteins - metabolism</topic><topic>Nuclear Proteins - physiology</topic><topic>Pharmacology. Drug treatments</topic><topic>RNA Interference</topic><topic>Signal Transduction</topic><topic>Tumor Burden</topic><topic>Tumor Suppressor Proteins - genetics</topic><topic>Tumor Suppressor Proteins - metabolism</topic><topic>Tumor Suppressor Proteins - physiology</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>TRONT, Jennifer S</creatorcontrib><creatorcontrib>YAJUE HUANG</creatorcontrib><creatorcontrib>FORNACE, Albert A</creatorcontrib><creatorcontrib>HOFFMAN, Barbara</creatorcontrib><creatorcontrib>LIEBERMANN, Dan A</creatorcontrib><collection>Pascal-Francis</collection><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><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>TRONT, Jennifer S</au><au>YAJUE HUANG</au><au>FORNACE, Albert A</au><au>HOFFMAN, Barbara</au><au>LIEBERMANN, Dan A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Gadd45a Functions as a Promoter or Suppressor of Breast Cancer Dependent on the Oncogenic Stress</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2010-12-01</date><risdate>2010</risdate><volume>70</volume><issue>23</issue><spage>9671</spage><epage>9681</epage><pages>9671-9681</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>Gadd45a plays a pivotal role as a stress sensor that modulates cellular responses to various stress stimuli including oncogenic stress. We reported that the stress sensor Gadd45a gene functions as a tumor suppressor in Ras-driven breast tumorigenesis via increasing JNK-mediated apoptosis and p38-mediated senescence. In contrast, here, we show that Gadd45a promotes Myc-driven breast cancer by negatively regulating MMP10 via GSK3 β/β-catenin signaling, resulting in increased tumor vascularization and growth. These novel findings indicate that Gadd45a functions as either tumor promoter or suppressor, is dependent on the oncogenic stress, and is mediated via distinct signaling pathways. Collectively, these novel findings highlight the significance of the type of oncogenic alteration on how stress response genes function during initiation and progression of tumorigenesis. 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| subjects | Animals Antineoplastic agents beta Catenin - metabolism Biological and medical sciences Blotting, Western Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell Cycle Proteins - physiology Female Gene Expression Regulation, Neoplastic Genes, myc - genetics Genes, myc - physiology Glycogen Synthase Kinase 3 - metabolism Glycogen Synthase Kinase 3 beta Gynecology. Andrology. Obstetrics Immunohistochemistry Male Mammary gland diseases Mammary Neoplasms, Animal - genetics Mammary Neoplasms, Animal - metabolism Mammary Neoplasms, Animal - pathology Matrix Metalloproteinase 10 - genetics Matrix Metalloproteinase 10 - metabolism Medical sciences Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Neovascularization, Pathologic - pathology Nuclear Proteins - genetics Nuclear Proteins - metabolism Nuclear Proteins - physiology Pharmacology. Drug treatments RNA Interference Signal Transduction Tumor Burden Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Tumor Suppressor Proteins - physiology Tumors |
| title | Gadd45a Functions as a Promoter or Suppressor of Breast Cancer Dependent on the Oncogenic Stress |
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