Reactive oxygen species via redox signaling to PI3K/AKT pathway contribute to the malignant growth of 4-hydroxy estradiol-transformed mammary epithelial cells
The purpose of this study was to investigate the effects of 17-β-estradiol (E2)-induced reactive oxygen species (ROS) on the induction of mammary tumorigenesis. We found that ROS-induced by repeated exposures to 4-hydroxy-estradiol (4-OH-E2), a predominant catechol metabolite of E2, caused transform...
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| description | The purpose of this study was to investigate the effects of 17-β-estradiol (E2)-induced reactive oxygen species (ROS) on the induction of mammary tumorigenesis. We found that ROS-induced by repeated exposures to 4-hydroxy-estradiol (4-OH-E2), a predominant catechol metabolite of E2, caused transformation of normal human mammary epithelial MCF-10A cells with malignant growth in nude mice. This was evident from inhibition of estrogen-induced breast tumor formation in the xenograft model by both overexpression of catalase as well as by co-treatment with Ebselen. To understand how 4-OH-E2 induces this malignant phenotype through ROS, we investigated the effects of 4-OH-E2 on redox-sensitive signal transduction pathways. During the malignant transformation process we observed that 4-OH-E2 treatment increased AKT phosphorylation through PI3K activation. The PI3K-mediated phosphorylation of AKT in 4-OH-E2-treated cells was inhibited by ROS modifiers as well as by silencing of AKT expression. RNA interference of AKT markedly inhibited 4-OH-E2-induced in vitro tumor formation. The expression of cell cycle genes, cdc2, PRC1 and PCNA and one of transcription factors that control the expression of these genes - nuclear respiratory factor-1 (NRF-1) was significantly up-regulated during the 4-OH-E2-mediated malignant transformation process. The increased expression of these genes was inhibited by ROS modifiers as well as by silencing of AKT expression. These results indicate that 4-OH-E2-induced cell transformation may be mediated, in part, through redox-sensitive AKT signal transduction pathways by up-regulating the expression of cell cycle genes cdc2, PRC1 and PCNA, and the transcription factor - NRF-1. In summary, our study has demonstrated that: (i) 4-OH-E2 is one of the main estrogen metabolites that induce mammary tumorigenesis and (ii) ROS-mediated signaling leading to the activation of PI3K/AKT pathway plays an important role in the generation of 4-OH-E2-induced malignant phenotype of breast epithelial cells. In conclusion, ROS are important signaling molecules in the development of estrogen-induced malignant breast lesions. |
| doi_str_mv | 10.1371/journal.pone.0054206 |
| format | Article |
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We found that ROS-induced by repeated exposures to 4-hydroxy-estradiol (4-OH-E2), a predominant catechol metabolite of E2, caused transformation of normal human mammary epithelial MCF-10A cells with malignant growth in nude mice. This was evident from inhibition of estrogen-induced breast tumor formation in the xenograft model by both overexpression of catalase as well as by co-treatment with Ebselen. To understand how 4-OH-E2 induces this malignant phenotype through ROS, we investigated the effects of 4-OH-E2 on redox-sensitive signal transduction pathways. During the malignant transformation process we observed that 4-OH-E2 treatment increased AKT phosphorylation through PI3K activation. The PI3K-mediated phosphorylation of AKT in 4-OH-E2-treated cells was inhibited by ROS modifiers as well as by silencing of AKT expression. RNA interference of AKT markedly inhibited 4-OH-E2-induced in vitro tumor formation. The expression of cell cycle genes, cdc2, PRC1 and PCNA and one of transcription factors that control the expression of these genes - nuclear respiratory factor-1 (NRF-1) was significantly up-regulated during the 4-OH-E2-mediated malignant transformation process. The increased expression of these genes was inhibited by ROS modifiers as well as by silencing of AKT expression. These results indicate that 4-OH-E2-induced cell transformation may be mediated, in part, through redox-sensitive AKT signal transduction pathways by up-regulating the expression of cell cycle genes cdc2, PRC1 and PCNA, and the transcription factor - NRF-1. In summary, our study has demonstrated that: (i) 4-OH-E2 is one of the main estrogen metabolites that induce mammary tumorigenesis and (ii) ROS-mediated signaling leading to the activation of PI3K/AKT pathway plays an important role in the generation of 4-OH-E2-induced malignant phenotype of breast epithelial cells. In conclusion, ROS are important signaling molecules in the development of estrogen-induced malignant breast lesions.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0054206</identifier><identifier>PMID: 23437041</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>1-Phosphatidylinositol 3-kinase ; 17β-Estradiol ; Activation ; AKT protein ; Animals ; Azoles - pharmacology ; Biology ; Breast ; Breast cancer ; Catalase ; Catalase - metabolism ; Catechin ; Catechol ; Catechols - metabolism ; Cdc2 protein ; Cell cycle ; Cell Cycle Proteins - genetics ; Cell Cycle Proteins - metabolism ; Cell Proliferation - drug effects ; Cell Transformation, Neoplastic - drug effects ; Cell Transformation, Neoplastic - pathology ; Cellular signal transduction ; Collagen - pharmacology ; Colony-Forming Units Assay ; Dose-Response Relationship, Drug ; Epithelial cells ; Epithelial Cells - enzymology ; Epithelial Cells - pathology ; Estradiol ; Estradiol - analogs & derivatives ; Estradiol - pharmacology ; Estrogens ; Estrogens, Catechol - pharmacology ; Fulvestrant ; Gene expression ; Gene Expression Regulation, Neoplastic - drug effects ; Genes ; Genetic transformation ; Growth ; Humans ; Isoindoles ; Kinases ; Lesions ; Mammary gland ; Mammary Glands, Human - drug effects ; Mammary Glands, Human - enzymology ; Mammary Glands, Human - pathology ; Medicine ; Metabolites ; Mice ; Models, Biological ; Neoplasm Invasiveness ; Organoselenium Compounds - pharmacology ; Oxidation-Reduction - drug effects ; Oxygen ; Phenotype ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphorylation ; Proliferating cell nuclear antigen ; Proto-Oncogene Proteins c-akt - metabolism ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Ribonucleic acid ; RNA ; RNA-mediated interference ; Sex hormones ; Signal processing ; Signal transduction ; Signal Transduction - drug effects ; Signal Transduction - genetics ; Signaling ; Spheroids, Cellular - drug effects ; Spheroids, Cellular - metabolism ; Spheroids, Cellular - pathology ; Transcription factors ; Transformation ; Tumorigenesis ; Xenografts</subject><ispartof>PloS one, 2013-02, Vol.8 (2), p.e54206</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Okoh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Okoh et al 2013 Okoh et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-32735ac534ddb26292dda55e20370d11bf98b801c90a8bbb8691f66a4245cad13</citedby><cites>FETCH-LOGICAL-c692t-32735ac534ddb26292dda55e20370d11bf98b801c90a8bbb8691f66a4245cad13</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/PMC3578838/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578838/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23437041$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Pani, Giovambattista</contributor><creatorcontrib>Okoh, Victor O</creatorcontrib><creatorcontrib>Felty, Quentin</creatorcontrib><creatorcontrib>Parkash, Jai</creatorcontrib><creatorcontrib>Poppiti, Robert</creatorcontrib><creatorcontrib>Roy, Deodutta</creatorcontrib><title>Reactive oxygen species via redox signaling to PI3K/AKT pathway contribute to the malignant growth of 4-hydroxy estradiol-transformed mammary epithelial cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The purpose of this study was to investigate the effects of 17-β-estradiol (E2)-induced reactive oxygen species (ROS) on the induction of mammary tumorigenesis. We found that ROS-induced by repeated exposures to 4-hydroxy-estradiol (4-OH-E2), a predominant catechol metabolite of E2, caused transformation of normal human mammary epithelial MCF-10A cells with malignant growth in nude mice. This was evident from inhibition of estrogen-induced breast tumor formation in the xenograft model by both overexpression of catalase as well as by co-treatment with Ebselen. To understand how 4-OH-E2 induces this malignant phenotype through ROS, we investigated the effects of 4-OH-E2 on redox-sensitive signal transduction pathways. During the malignant transformation process we observed that 4-OH-E2 treatment increased AKT phosphorylation through PI3K activation. The PI3K-mediated phosphorylation of AKT in 4-OH-E2-treated cells was inhibited by ROS modifiers as well as by silencing of AKT expression. RNA interference of AKT markedly inhibited 4-OH-E2-induced in vitro tumor formation. The expression of cell cycle genes, cdc2, PRC1 and PCNA and one of transcription factors that control the expression of these genes - nuclear respiratory factor-1 (NRF-1) was significantly up-regulated during the 4-OH-E2-mediated malignant transformation process. The increased expression of these genes was inhibited by ROS modifiers as well as by silencing of AKT expression. These results indicate that 4-OH-E2-induced cell transformation may be mediated, in part, through redox-sensitive AKT signal transduction pathways by up-regulating the expression of cell cycle genes cdc2, PRC1 and PCNA, and the transcription factor - NRF-1. In summary, our study has demonstrated that: (i) 4-OH-E2 is one of the main estrogen metabolites that induce mammary tumorigenesis and (ii) ROS-mediated signaling leading to the activation of PI3K/AKT pathway plays an important role in the generation of 4-OH-E2-induced malignant phenotype of breast epithelial cells. In conclusion, ROS are important signaling molecules in the development of estrogen-induced malignant breast lesions.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>17β-Estradiol</subject><subject>Activation</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Azoles - pharmacology</subject><subject>Biology</subject><subject>Breast</subject><subject>Breast cancer</subject><subject>Catalase</subject><subject>Catalase - metabolism</subject><subject>Catechin</subject><subject>Catechol</subject><subject>Catechols - metabolism</subject><subject>Cdc2 protein</subject><subject>Cell cycle</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Transformation, Neoplastic - drug effects</subject><subject>Cell Transformation, Neoplastic - pathology</subject><subject>Cellular signal transduction</subject><subject>Collagen - pharmacology</subject><subject>Colony-Forming Units Assay</subject><subject>Dose-Response Relationship, Drug</subject><subject>Epithelial cells</subject><subject>Epithelial Cells - enzymology</subject><subject>Epithelial Cells - pathology</subject><subject>Estradiol</subject><subject>Estradiol - analogs & derivatives</subject><subject>Estradiol - pharmacology</subject><subject>Estrogens</subject><subject>Estrogens, Catechol - pharmacology</subject><subject>Fulvestrant</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Genes</subject><subject>Genetic transformation</subject><subject>Growth</subject><subject>Humans</subject><subject>Isoindoles</subject><subject>Kinases</subject><subject>Lesions</subject><subject>Mammary gland</subject><subject>Mammary Glands, Human - drug effects</subject><subject>Mammary Glands, Human - enzymology</subject><subject>Mammary Glands, Human - pathology</subject><subject>Medicine</subject><subject>Metabolites</subject><subject>Mice</subject><subject>Models, Biological</subject><subject>Neoplasm Invasiveness</subject><subject>Organoselenium Compounds - pharmacology</subject><subject>Oxidation-Reduction - drug effects</subject><subject>Oxygen</subject><subject>Phenotype</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphorylation</subject><subject>Proliferating cell nuclear antigen</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA-mediated interference</subject><subject>Sex hormones</subject><subject>Signal processing</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - genetics</subject><subject>Signaling</subject><subject>Spheroids, Cellular - drug effects</subject><subject>Spheroids, Cellular - metabolism</subject><subject>Spheroids, Cellular - pathology</subject><subject>Transcription factors</subject><subject>Transformation</subject><subject>Tumorigenesis</subject><subject>Xenografts</subject><issn>1932-6203</issn><issn>1932-6203</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><sourceid>DOA</sourceid><recordid>eNqNk21r2zAQx83YWLtu32BsgsFgL5xalh_fDELZQ2iho-v2VsjS2VZQrFRS0uTL7LPusrglgQ2GDTK63_9_p5Mvil7TZEJZSc_nduUGYSZLO8AkSfIsTYon0SmtWRoXacKeHnyfRC-8nyPEqqJ4Hp2kLGNlktHT6NcNCBn0GojdbDsYiF-C1ODJWgviQNkN8brDPHroSLDk24xdnk8vb8lShP5ebIm0Q3C6WQXYhUMPZIEwKoZAOmfvQ09sS7K43yqHKQj44ITS1sS4Dr61bgEKNYuFcBhdarQwWhgiwRj_MnrWCuPh1bieRT8-f7q9-BpfXX-ZXUyvYlnUaYhZWrJcyJxlSjVpkdapUiLPAY9eJorSpq2rpkqorBNRNU1TFTVti0JkaZZLoSg7i97ufZfGej621nPKcnzLMs-QmO0JZcWcL53e1cut0PzPhnUdFy5oaYDjXYBUaQ1FCxkIJaocijrPcrw20cgavT6O2VYNnl4CtlCYI9PjyKB73tk1x1qqilVo8G40cPZuhS39R8kj1QmsSg-tRTO50F7yaVZWtEoRRWryFwofBQuNtwutxv0jwYcjwe4PgE3oxMp7Pvt-8__s9c9j9v0B24MwoffWrIK2gz8Gsz0onfXeQfvYOZrw3Ww8dIPvZoOPs4GyN4ddfxQ9DAP7DVezDKI</recordid><startdate>20130221</startdate><enddate>20130221</enddate><creator>Okoh, Victor O</creator><creator>Felty, Quentin</creator><creator>Parkash, Jai</creator><creator>Poppiti, Robert</creator><creator>Roy, Deodutta</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130221</creationdate><title>Reactive oxygen species via redox signaling to PI3K/AKT pathway contribute to the malignant growth of 4-hydroxy estradiol-transformed mammary epithelial cells</title><author>Okoh, Victor O ; Felty, Quentin ; Parkash, Jai ; Poppiti, Robert ; Roy, Deodutta</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-32735ac534ddb26292dda55e20370d11bf98b801c90a8bbb8691f66a4245cad13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>17β-Estradiol</topic><topic>Activation</topic><topic>AKT protein</topic><topic>Animals</topic><topic>Azoles - pharmacology</topic><topic>Biology</topic><topic>Breast</topic><topic>Breast cancer</topic><topic>Catalase</topic><topic>Catalase - metabolism</topic><topic>Catechin</topic><topic>Catechol</topic><topic>Catechols - metabolism</topic><topic>Cdc2 protein</topic><topic>Cell cycle</topic><topic>Cell Cycle Proteins - genetics</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Transformation, Neoplastic - drug effects</topic><topic>Cell Transformation, Neoplastic - pathology</topic><topic>Cellular signal transduction</topic><topic>Collagen - pharmacology</topic><topic>Colony-Forming Units Assay</topic><topic>Dose-Response Relationship, Drug</topic><topic>Epithelial cells</topic><topic>Epithelial Cells - enzymology</topic><topic>Epithelial Cells - pathology</topic><topic>Estradiol</topic><topic>Estradiol - analogs & derivatives</topic><topic>Estradiol - pharmacology</topic><topic>Estrogens</topic><topic>Estrogens, Catechol - pharmacology</topic><topic>Fulvestrant</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Genes</topic><topic>Genetic transformation</topic><topic>Growth</topic><topic>Humans</topic><topic>Isoindoles</topic><topic>Kinases</topic><topic>Lesions</topic><topic>Mammary gland</topic><topic>Mammary Glands, Human - drug effects</topic><topic>Mammary Glands, Human - enzymology</topic><topic>Mammary Glands, Human - pathology</topic><topic>Medicine</topic><topic>Metabolites</topic><topic>Mice</topic><topic>Models, Biological</topic><topic>Neoplasm Invasiveness</topic><topic>Organoselenium Compounds - pharmacology</topic><topic>Oxidation-Reduction - drug effects</topic><topic>Oxygen</topic><topic>Phenotype</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphorylation</topic><topic>Proliferating cell nuclear antigen</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Reactive oxygen species</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA-mediated interference</topic><topic>Sex hormones</topic><topic>Signal processing</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - genetics</topic><topic>Signaling</topic><topic>Spheroids, Cellular - drug effects</topic><topic>Spheroids, Cellular - metabolism</topic><topic>Spheroids, Cellular - pathology</topic><topic>Transcription factors</topic><topic>Transformation</topic><topic>Tumorigenesis</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Okoh, Victor O</creatorcontrib><creatorcontrib>Felty, Quentin</creatorcontrib><creatorcontrib>Parkash, Jai</creatorcontrib><creatorcontrib>Poppiti, Robert</creatorcontrib><creatorcontrib>Roy, Deodutta</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Okoh, Victor O</au><au>Felty, Quentin</au><au>Parkash, Jai</au><au>Poppiti, Robert</au><au>Roy, Deodutta</au><au>Pani, Giovambattista</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Reactive oxygen species via redox signaling to PI3K/AKT pathway contribute to the malignant growth of 4-hydroxy estradiol-transformed mammary epithelial cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-02-21</date><risdate>2013</risdate><volume>8</volume><issue>2</issue><spage>e54206</spage><pages>e54206-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The purpose of this study was to investigate the effects of 17-β-estradiol (E2)-induced reactive oxygen species (ROS) on the induction of mammary tumorigenesis. We found that ROS-induced by repeated exposures to 4-hydroxy-estradiol (4-OH-E2), a predominant catechol metabolite of E2, caused transformation of normal human mammary epithelial MCF-10A cells with malignant growth in nude mice. This was evident from inhibition of estrogen-induced breast tumor formation in the xenograft model by both overexpression of catalase as well as by co-treatment with Ebselen. To understand how 4-OH-E2 induces this malignant phenotype through ROS, we investigated the effects of 4-OH-E2 on redox-sensitive signal transduction pathways. During the malignant transformation process we observed that 4-OH-E2 treatment increased AKT phosphorylation through PI3K activation. The PI3K-mediated phosphorylation of AKT in 4-OH-E2-treated cells was inhibited by ROS modifiers as well as by silencing of AKT expression. RNA interference of AKT markedly inhibited 4-OH-E2-induced in vitro tumor formation. The expression of cell cycle genes, cdc2, PRC1 and PCNA and one of transcription factors that control the expression of these genes - nuclear respiratory factor-1 (NRF-1) was significantly up-regulated during the 4-OH-E2-mediated malignant transformation process. The increased expression of these genes was inhibited by ROS modifiers as well as by silencing of AKT expression. These results indicate that 4-OH-E2-induced cell transformation may be mediated, in part, through redox-sensitive AKT signal transduction pathways by up-regulating the expression of cell cycle genes cdc2, PRC1 and PCNA, and the transcription factor - NRF-1. In summary, our study has demonstrated that: (i) 4-OH-E2 is one of the main estrogen metabolites that induce mammary tumorigenesis and (ii) ROS-mediated signaling leading to the activation of PI3K/AKT pathway plays an important role in the generation of 4-OH-E2-induced malignant phenotype of breast epithelial cells. In conclusion, ROS are important signaling molecules in the development of estrogen-induced malignant breast lesions.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23437041</pmid><doi>10.1371/journal.pone.0054206</doi><tpages>e54206</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-02, Vol.8 (2), p.e54206 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1351357754 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 1-Phosphatidylinositol 3-kinase 17β-Estradiol Activation AKT protein Animals Azoles - pharmacology Biology Breast Breast cancer Catalase Catalase - metabolism Catechin Catechol Catechols - metabolism Cdc2 protein Cell cycle Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell Proliferation - drug effects Cell Transformation, Neoplastic - drug effects Cell Transformation, Neoplastic - pathology Cellular signal transduction Collagen - pharmacology Colony-Forming Units Assay Dose-Response Relationship, Drug Epithelial cells Epithelial Cells - enzymology Epithelial Cells - pathology Estradiol Estradiol - analogs & derivatives Estradiol - pharmacology Estrogens Estrogens, Catechol - pharmacology Fulvestrant Gene expression Gene Expression Regulation, Neoplastic - drug effects Genes Genetic transformation Growth Humans Isoindoles Kinases Lesions Mammary gland Mammary Glands, Human - drug effects Mammary Glands, Human - enzymology Mammary Glands, Human - pathology Medicine Metabolites Mice Models, Biological Neoplasm Invasiveness Organoselenium Compounds - pharmacology Oxidation-Reduction - drug effects Oxygen Phenotype Phosphatidylinositol 3-Kinases - metabolism Phosphorylation Proliferating cell nuclear antigen Proto-Oncogene Proteins c-akt - metabolism Reactive oxygen species Reactive Oxygen Species - metabolism Ribonucleic acid RNA RNA-mediated interference Sex hormones Signal processing Signal transduction Signal Transduction - drug effects Signal Transduction - genetics Signaling Spheroids, Cellular - drug effects Spheroids, Cellular - metabolism Spheroids, Cellular - pathology Transcription factors Transformation Tumorigenesis Xenografts |
| title | Reactive oxygen species via redox signaling to PI3K/AKT pathway contribute to the malignant growth of 4-hydroxy estradiol-transformed mammary epithelial cells |
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