Chronic exposure to combined carcinogens enhances breast cell carcinogenesis with mesenchymal and stem-like cell properties
Breast cancer is the most common type of cancer affecting women in North America and Europe. More than 85% of breast cancers are sporadic and attributable to long-term exposure to small quantities of multiple carcinogens. To understand how multiple carcinogens act together to induce cellular carcino...
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| description | Breast cancer is the most common type of cancer affecting women in North America and Europe. More than 85% of breast cancers are sporadic and attributable to long-term exposure to small quantities of multiple carcinogens. To understand how multiple carcinogens act together to induce cellular carcinogenesis, we studied the activity of environmental carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P), and dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) using our breast cell carcinogenesis model. Our study revealed, for the first time, that combined NNK and B[a]P enhanced breast cell carcinogenesis chronically induced by PhIP in both non-cancerous and cancerous breast cells. Co-exposure was more potent than sequential exposure to combined NNK and B[a]P followed by PhIP in inducing carcinogenesis. Initiation of carcinogenesis was measured by transient endpoints induced in a single exposure, while progression of carcinogenesis was measured by acquisition of constitutive endpoints in cumulative exposures. Transient endpoints included DNA damage, Ras-Erk-Nox pathway activation, reactive oxygen species elevation, and increased cellular proliferation. Constitutive endpoints included various cancer-associated properties and signaling modulators, as well as enrichment of cancer stem-like cell population and activation of the epithelial-to-mesenchymal transition program. Using transient and constitutive endpoints as targets, we detected that a combination of the green tea catechins ECG and EGCG, at non-cytotoxic levels, was more effective than individual agents in intervention of cellular carcinogenesis induced by combined NNK, B[a]P, and PhIP. Thus, use of combined ECG and EGCG should be seriously considered for early intervention of breast cell carcinogenesis associated with long-term exposure to environmental and dietary carcinogens. |
| doi_str_mv | 10.1371/journal.pone.0108698 |
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More than 85% of breast cancers are sporadic and attributable to long-term exposure to small quantities of multiple carcinogens. To understand how multiple carcinogens act together to induce cellular carcinogenesis, we studied the activity of environmental carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P), and dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) using our breast cell carcinogenesis model. Our study revealed, for the first time, that combined NNK and B[a]P enhanced breast cell carcinogenesis chronically induced by PhIP in both non-cancerous and cancerous breast cells. Co-exposure was more potent than sequential exposure to combined NNK and B[a]P followed by PhIP in inducing carcinogenesis. Initiation of carcinogenesis was measured by transient endpoints induced in a single exposure, while progression of carcinogenesis was measured by acquisition of constitutive endpoints in cumulative exposures. Transient endpoints included DNA damage, Ras-Erk-Nox pathway activation, reactive oxygen species elevation, and increased cellular proliferation. Constitutive endpoints included various cancer-associated properties and signaling modulators, as well as enrichment of cancer stem-like cell population and activation of the epithelial-to-mesenchymal transition program. Using transient and constitutive endpoints as targets, we detected that a combination of the green tea catechins ECG and EGCG, at non-cytotoxic levels, was more effective than individual agents in intervention of cellular carcinogenesis induced by combined NNK, B[a]P, and PhIP. Thus, use of combined ECG and EGCG should be seriously considered for early intervention of breast cell carcinogenesis associated with long-term exposure to environmental and dietary carcinogens.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0108698</identifier><identifier>PMID: 25372613</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone ; Analysis ; Benzo(a)pyrene ; Benzo(a)pyrene - pharmacology ; Benzopyrene ; Biology and Life Sciences ; Breast cancer ; Breast Neoplasms - metabolism ; Cancer ; Carcinogenesis ; Carcinogenesis - drug effects ; Carcinogenesis - metabolism ; Carcinogens ; Carcinogens - pharmacology ; Catechin ; Cell activation ; Chronic exposure ; Cytotoxicity ; Deoxyribonucleic acid ; Diet ; DNA ; DNA Damage ; Drug dosages ; Drug Synergism ; Electrocardiography ; Epigallocatechin gallate ; Epigallocatechin-3-gallate ; Epithelial-Mesenchymal Transition - drug effects ; Exposure ; Extracellular Signal-Regulated MAP Kinases - metabolism ; Genomes ; Green tea ; Humans ; Imidazoles - pharmacology ; Intervention ; MCF-7 Cells ; Medicine and Health Sciences ; Mesenchyme ; Modulators ; NADPH Oxidases - metabolism ; Nitrosamines - pharmacology ; Oxygen ; Pyrene ; Pyridines ; ras Proteins - metabolism ; Reactive Oxygen Species ; Rodents ; Signal Transduction ; Signaling ; Stem cells ; Target detection ; Tea ; Veterinary colleges ; Veterinary medicine</subject><ispartof>PloS one, 2014-11, Vol.9 (11), p.e108698</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Pluchino, Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://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>2014 Pluchino, Wang 2014 Pluchino, Wang</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c622t-546161c0b6a535f006d422b06b6449e12d39aff643e1a0359ef330126af218d93</citedby><cites>FETCH-LOGICAL-c622t-546161c0b6a535f006d422b06b6449e12d39aff643e1a0359ef330126af218d93</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/PMC4220909/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220909/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,862,883,2098,2917,23849,27907,27908,53774,53776,79351,79352</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25372613$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Glynn, Sharon A.</contributor><creatorcontrib>Pluchino, Lenora Ann</creatorcontrib><creatorcontrib>Wang, Hwa-Chain Robert</creatorcontrib><title>Chronic exposure to combined carcinogens enhances breast cell carcinogenesis with mesenchymal and stem-like cell properties</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Breast cancer is the most common type of cancer affecting women in North America and Europe. More than 85% of breast cancers are sporadic and attributable to long-term exposure to small quantities of multiple carcinogens. To understand how multiple carcinogens act together to induce cellular carcinogenesis, we studied the activity of environmental carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P), and dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) using our breast cell carcinogenesis model. Our study revealed, for the first time, that combined NNK and B[a]P enhanced breast cell carcinogenesis chronically induced by PhIP in both non-cancerous and cancerous breast cells. Co-exposure was more potent than sequential exposure to combined NNK and B[a]P followed by PhIP in inducing carcinogenesis. Initiation of carcinogenesis was measured by transient endpoints induced in a single exposure, while progression of carcinogenesis was measured by acquisition of constitutive endpoints in cumulative exposures. Transient endpoints included DNA damage, Ras-Erk-Nox pathway activation, reactive oxygen species elevation, and increased cellular proliferation. Constitutive endpoints included various cancer-associated properties and signaling modulators, as well as enrichment of cancer stem-like cell population and activation of the epithelial-to-mesenchymal transition program. Using transient and constitutive endpoints as targets, we detected that a combination of the green tea catechins ECG and EGCG, at non-cytotoxic levels, was more effective than individual agents in intervention of cellular carcinogenesis induced by combined NNK, B[a]P, and PhIP. 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drug effects</subject><subject>Exposure</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>Genomes</subject><subject>Green tea</subject><subject>Humans</subject><subject>Imidazoles - pharmacology</subject><subject>Intervention</subject><subject>MCF-7 Cells</subject><subject>Medicine and Health Sciences</subject><subject>Mesenchyme</subject><subject>Modulators</subject><subject>NADPH Oxidases - metabolism</subject><subject>Nitrosamines - pharmacology</subject><subject>Oxygen</subject><subject>Pyrene</subject><subject>Pyridines</subject><subject>ras Proteins - metabolism</subject><subject>Reactive Oxygen Species</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>Stem cells</subject><subject>Target detection</subject><subject>Tea</subject><subject>Veterinary colleges</subject><subject>Veterinary medicine</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</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>eNqNkl2L1DAYhYso7rr6D0QLguDFjPlo0_ZGWBY_BhYW_LoNafpmmjFNapLqLv55M053mYKC9KLl7XNO3hxOlj3FaI1phV_v3OStMOvRWVgjjGrW1PeyU9xQsmIE0ftH3yfZoxB2CJW0ZuxhdkJKWhGG6Wn266L3zmqZw_XowuQhjy6Xbmi1hS6Xwktt3RZsyMH2wkoIeetBhJhLMOYIgKBD_lPHPh8ggJX9zSBMLmyXhwjDyuhvcJCM3o3go4bwOHughAnwZH6fZV_evf188WF1efV-c3F-uZKMkLgqC4YZlqhloqSlQoh1BSEtYi0rigYw6WgjlGIFBSwQLRtQlCJMmFAE111Dz7LnB9_RuMDn3ALHKZmyKXGNE7E5EJ0TOz56PQh_w53Q_M_A-S0XaWVpgFe0FqqgSLGmLMqG1KSthKRd1bZVXYm915v5tKkdoJNgoxdmYbr8Y3XPt-4HT5dCDdqv-2I28O77BCH-Y-WZ2oq0lbbKJTM56CD5eYHrClUMF4la_4VKTweDlqk5Sqf5QvBqIUhMhOu4FVMIfPPp4_-zV1-X7MsjtgdhYh-cmaJ2NizB4gBK70LwoO6Sw4jvi3-bBt8Xn8_FT7Jnx6nfiW6bTn8DjD3-0A</recordid><startdate>20141105</startdate><enddate>20141105</enddate><creator>Pluchino, Lenora Ann</creator><creator>Wang, Hwa-Chain Robert</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>AEUYN</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>20141105</creationdate><title>Chronic exposure to combined carcinogens enhances breast cell carcinogenesis with mesenchymal and stem-like cell properties</title><author>Pluchino, Lenora Ann ; Wang, Hwa-Chain Robert</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c622t-546161c0b6a535f006d422b06b6449e12d39aff643e1a0359ef330126af218d93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone</topic><topic>Analysis</topic><topic>Benzo(a)pyrene</topic><topic>Benzo(a)pyrene - pharmacology</topic><topic>Benzopyrene</topic><topic>Biology and Life Sciences</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - metabolism</topic><topic>Cancer</topic><topic>Carcinogenesis</topic><topic>Carcinogenesis - drug effects</topic><topic>Carcinogenesis - metabolism</topic><topic>Carcinogens</topic><topic>Carcinogens - pharmacology</topic><topic>Catechin</topic><topic>Cell activation</topic><topic>Chronic exposure</topic><topic>Cytotoxicity</topic><topic>Deoxyribonucleic acid</topic><topic>Diet</topic><topic>DNA</topic><topic>DNA Damage</topic><topic>Drug dosages</topic><topic>Drug Synergism</topic><topic>Electrocardiography</topic><topic>Epigallocatechin gallate</topic><topic>Epigallocatechin-3-gallate</topic><topic>Epithelial-Mesenchymal Transition - drug effects</topic><topic>Exposure</topic><topic>Extracellular Signal-Regulated MAP Kinases - metabolism</topic><topic>Genomes</topic><topic>Green tea</topic><topic>Humans</topic><topic>Imidazoles - pharmacology</topic><topic>Intervention</topic><topic>MCF-7 Cells</topic><topic>Medicine and Health Sciences</topic><topic>Mesenchyme</topic><topic>Modulators</topic><topic>NADPH Oxidases - 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More than 85% of breast cancers are sporadic and attributable to long-term exposure to small quantities of multiple carcinogens. To understand how multiple carcinogens act together to induce cellular carcinogenesis, we studied the activity of environmental carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P), and dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) using our breast cell carcinogenesis model. Our study revealed, for the first time, that combined NNK and B[a]P enhanced breast cell carcinogenesis chronically induced by PhIP in both non-cancerous and cancerous breast cells. Co-exposure was more potent than sequential exposure to combined NNK and B[a]P followed by PhIP in inducing carcinogenesis. Initiation of carcinogenesis was measured by transient endpoints induced in a single exposure, while progression of carcinogenesis was measured by acquisition of constitutive endpoints in cumulative exposures. Transient endpoints included DNA damage, Ras-Erk-Nox pathway activation, reactive oxygen species elevation, and increased cellular proliferation. Constitutive endpoints included various cancer-associated properties and signaling modulators, as well as enrichment of cancer stem-like cell population and activation of the epithelial-to-mesenchymal transition program. Using transient and constitutive endpoints as targets, we detected that a combination of the green tea catechins ECG and EGCG, at non-cytotoxic levels, was more effective than individual agents in intervention of cellular carcinogenesis induced by combined NNK, B[a]P, and PhIP. Thus, use of combined ECG and EGCG should be seriously considered for early intervention of breast cell carcinogenesis associated with long-term exposure to environmental and dietary carcinogens.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25372613</pmid><doi>10.1371/journal.pone.0108698</doi><oa>free_for_read</oa></addata></record> |
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| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1620595181 |
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| subjects | 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Analysis Benzo(a)pyrene Benzo(a)pyrene - pharmacology Benzopyrene Biology and Life Sciences Breast cancer Breast Neoplasms - metabolism Cancer Carcinogenesis Carcinogenesis - drug effects Carcinogenesis - metabolism Carcinogens Carcinogens - pharmacology Catechin Cell activation Chronic exposure Cytotoxicity Deoxyribonucleic acid Diet DNA DNA Damage Drug dosages Drug Synergism Electrocardiography Epigallocatechin gallate Epigallocatechin-3-gallate Epithelial-Mesenchymal Transition - drug effects Exposure Extracellular Signal-Regulated MAP Kinases - metabolism Genomes Green tea Humans Imidazoles - pharmacology Intervention MCF-7 Cells Medicine and Health Sciences Mesenchyme Modulators NADPH Oxidases - metabolism Nitrosamines - pharmacology Oxygen Pyrene Pyridines ras Proteins - metabolism Reactive Oxygen Species Rodents Signal Transduction Signaling Stem cells Target detection Tea Veterinary colleges Veterinary medicine |
| title | Chronic exposure to combined carcinogens enhances breast cell carcinogenesis with mesenchymal and stem-like cell properties |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-16T18%3A48%3A18IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Chronic%20exposure%20to%20combined%20carcinogens%20enhances%20breast%20cell%20carcinogenesis%20with%20mesenchymal%20and%20stem-like%20cell%20properties&rft.jtitle=PloS%20one&rft.au=Pluchino,%20Lenora%20Ann&rft.date=2014-11-05&rft.volume=9&rft.issue=11&rft.spage=e108698&rft.pages=e108698-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0108698&rft_dat=%3Cgale_plos_%3EA418707614%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1620595181&rft_id=info:pmid/25372613&rft_galeid=A418707614&rft_doaj_id=oai_doaj_org_article_738af430f695459282b7ac3d7bb787a1&rfr_iscdi=true |