Glyceollin I Reverses Epithelial to Mesenchymal Transition in Letrozole Resistant Breast Cancer through ZEB1
Although aromatase inhibitors are standard endocrine therapy for postmenopausal women with early-stage metastatic estrogen-dependent breast cancer, they are limited by the development of drug resistance. A better understanding of this process is critical towards designing novel strategies for diseas...
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| Veröffentlicht in: | International journal of environmental research and public health 2015-12, Vol.13 (1), p.ijerph13010010-ijerph13010010 |
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| creator | Carriere, Patrick P Llopis, Shawn D Naiki, Anna C Nguyen, Gina Phan, Tina Nguyen, Mary M Preyan, Lynez C Yearby, Letitia Pratt, Jamal Burks, Hope Davenport, Ian R Nguyen, Thu A Parker-Lemieux, KiTani Payton-Stewart, Florastina Williams, Christopher C Boué, Stephen M Burow, Matthew E Collins-Burow, Bridgette Hilliard, Aaron Davidson, A Michael Tilghman, Syreeta L |
| description | Although aromatase inhibitors are standard endocrine therapy for postmenopausal women with early-stage metastatic estrogen-dependent breast cancer, they are limited by the development of drug resistance. A better understanding of this process is critical towards designing novel strategies for disease management. Previously, we demonstrated a global proteomic signature of letrozole-resistance associated with hormone-independence, enhanced cell motility and implications of epithelial mesenchymal transition (EMT). Letrozole-resistant breast cancer cells (LTLT-Ca) were treated with a novel phytoalexin, glyceollin I, and exhibited morphological characteristics synonymous with an epithelial phenotype and decreased proliferation. Letrozole-resistance increased Zinc Finger E-Box Binding Homeobox 1 (ZEB1) expression (4.51-fold), while glyceollin I treatment caused a -3.39-fold reduction. Immunofluorescence analyses resulted of glyceollin I-induced increase and decrease in E-cadherin and ZEB1, respectively. In vivo studies performed in ovariectomized, female nude mice indicated that glyceollin treated tumors stained weakly for ZEB1 and N-cadherin and strongly for E-cadherin. Compared to letrozole-sensitive cells, LTLT-Ca cells displayed enhanced motility, however in the presence of glyceollin I, exhibited a 68% and 83% decrease in invasion and migration, respectively. These effects of glyceollin I were mediated in part by inhibition of ZEB1, thus indicating therapeutic potential of glyceollin I in targeting EMT in letrozole resistant breast cancer. |
| doi_str_mv | 10.3390/ijerph13010010 |
| format | Article |
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A better understanding of this process is critical towards designing novel strategies for disease management. Previously, we demonstrated a global proteomic signature of letrozole-resistance associated with hormone-independence, enhanced cell motility and implications of epithelial mesenchymal transition (EMT). Letrozole-resistant breast cancer cells (LTLT-Ca) were treated with a novel phytoalexin, glyceollin I, and exhibited morphological characteristics synonymous with an epithelial phenotype and decreased proliferation. Letrozole-resistance increased Zinc Finger E-Box Binding Homeobox 1 (ZEB1) expression (4.51-fold), while glyceollin I treatment caused a -3.39-fold reduction. Immunofluorescence analyses resulted of glyceollin I-induced increase and decrease in E-cadherin and ZEB1, respectively. In vivo studies performed in ovariectomized, female nude mice indicated that glyceollin treated tumors stained weakly for ZEB1 and N-cadherin and strongly for E-cadherin. Compared to letrozole-sensitive cells, LTLT-Ca cells displayed enhanced motility, however in the presence of glyceollin I, exhibited a 68% and 83% decrease in invasion and migration, respectively. These effects of glyceollin I were mediated in part by inhibition of ZEB1, thus indicating therapeutic potential of glyceollin I in targeting EMT in letrozole resistant breast cancer.</description><identifier>ISSN: 1660-4601</identifier><identifier>ISSN: 1661-7827</identifier><identifier>EISSN: 1660-4601</identifier><identifier>DOI: 10.3390/ijerph13010010</identifier><identifier>PMID: 26703648</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Animals ; Antineoplastic Agents - metabolism ; Antineoplastic Agents - therapeutic use ; Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - physiopathology ; Cell Line, Tumor - drug effects ; Cell Movement ; Drug Resistance, Neoplasm - drug effects ; Epithelial-Mesenchymal Transition - drug effects ; Female ; Fluorescence ; Genotype & phenotype ; Humans ; Metastasis ; Mice ; Mice, Nude ; Nitriles - metabolism ; Nitriles - therapeutic use ; Pterocarpans - metabolism ; Transcription Factors - metabolism ; Triazoles - metabolism ; Triazoles - therapeutic use</subject><ispartof>International journal of environmental research and public health, 2015-12, Vol.13 (1), p.ijerph13010010-ijerph13010010</ispartof><rights>Copyright Molecular Diversity Preservation International Jan 2016</rights><rights>2015 by the authors; licensee MDPI, Basel, Switzerland. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c517t-3f35a242a5475238c82c9f82c18e18f6e507e80f9860ea9e8070fd676a7c09a23</citedby><cites>FETCH-LOGICAL-c517t-3f35a242a5475238c82c9f82c18e18f6e507e80f9860ea9e8070fd676a7c09a23</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/PMC4730401/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4730401/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26703648$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Carriere, Patrick P</creatorcontrib><creatorcontrib>Llopis, Shawn D</creatorcontrib><creatorcontrib>Naiki, Anna C</creatorcontrib><creatorcontrib>Nguyen, Gina</creatorcontrib><creatorcontrib>Phan, Tina</creatorcontrib><creatorcontrib>Nguyen, Mary M</creatorcontrib><creatorcontrib>Preyan, Lynez C</creatorcontrib><creatorcontrib>Yearby, Letitia</creatorcontrib><creatorcontrib>Pratt, Jamal</creatorcontrib><creatorcontrib>Burks, Hope</creatorcontrib><creatorcontrib>Davenport, Ian R</creatorcontrib><creatorcontrib>Nguyen, Thu A</creatorcontrib><creatorcontrib>Parker-Lemieux, KiTani</creatorcontrib><creatorcontrib>Payton-Stewart, Florastina</creatorcontrib><creatorcontrib>Williams, Christopher C</creatorcontrib><creatorcontrib>Boué, Stephen M</creatorcontrib><creatorcontrib>Burow, Matthew E</creatorcontrib><creatorcontrib>Collins-Burow, Bridgette</creatorcontrib><creatorcontrib>Hilliard, Aaron</creatorcontrib><creatorcontrib>Davidson, A Michael</creatorcontrib><creatorcontrib>Tilghman, Syreeta L</creatorcontrib><title>Glyceollin I Reverses Epithelial to Mesenchymal Transition in Letrozole Resistant Breast Cancer through ZEB1</title><title>International journal of environmental research and public health</title><addtitle>Int J Environ Res Public Health</addtitle><description>Although aromatase inhibitors are standard endocrine therapy for postmenopausal women with early-stage metastatic estrogen-dependent breast cancer, they are limited by the development of drug resistance. A better understanding of this process is critical towards designing novel strategies for disease management. Previously, we demonstrated a global proteomic signature of letrozole-resistance associated with hormone-independence, enhanced cell motility and implications of epithelial mesenchymal transition (EMT). Letrozole-resistant breast cancer cells (LTLT-Ca) were treated with a novel phytoalexin, glyceollin I, and exhibited morphological characteristics synonymous with an epithelial phenotype and decreased proliferation. Letrozole-resistance increased Zinc Finger E-Box Binding Homeobox 1 (ZEB1) expression (4.51-fold), while glyceollin I treatment caused a -3.39-fold reduction. Immunofluorescence analyses resulted of glyceollin I-induced increase and decrease in E-cadherin and ZEB1, respectively. In vivo studies performed in ovariectomized, female nude mice indicated that glyceollin treated tumors stained weakly for ZEB1 and N-cadherin and strongly for E-cadherin. Compared to letrozole-sensitive cells, LTLT-Ca cells displayed enhanced motility, however in the presence of glyceollin I, exhibited a 68% and 83% decrease in invasion and migration, respectively. These effects of glyceollin I were mediated in part by inhibition of ZEB1, thus indicating therapeutic potential of glyceollin I in targeting EMT in letrozole resistant breast cancer.</description><subject>Animals</subject><subject>Antineoplastic Agents - metabolism</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - physiopathology</subject><subject>Cell Line, Tumor - drug effects</subject><subject>Cell Movement</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Epithelial-Mesenchymal Transition - drug effects</subject><subject>Female</subject><subject>Fluorescence</subject><subject>Genotype & phenotype</subject><subject>Humans</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Nitriles - metabolism</subject><subject>Nitriles - therapeutic use</subject><subject>Pterocarpans - metabolism</subject><subject>Transcription Factors - 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metabolism</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - physiopathology</topic><topic>Cell Line, Tumor - drug effects</topic><topic>Cell Movement</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Epithelial-Mesenchymal Transition - drug effects</topic><topic>Female</topic><topic>Fluorescence</topic><topic>Genotype & phenotype</topic><topic>Humans</topic><topic>Metastasis</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Nitriles - metabolism</topic><topic>Nitriles - therapeutic use</topic><topic>Pterocarpans - metabolism</topic><topic>Transcription Factors - metabolism</topic><topic>Triazoles - metabolism</topic><topic>Triazoles - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Carriere, Patrick P</creatorcontrib><creatorcontrib>Llopis, Shawn D</creatorcontrib><creatorcontrib>Naiki, Anna C</creatorcontrib><creatorcontrib>Nguyen, Gina</creatorcontrib><creatorcontrib>Phan, Tina</creatorcontrib><creatorcontrib>Nguyen, Mary M</creatorcontrib><creatorcontrib>Preyan, Lynez C</creatorcontrib><creatorcontrib>Yearby, Letitia</creatorcontrib><creatorcontrib>Pratt, Jamal</creatorcontrib><creatorcontrib>Burks, Hope</creatorcontrib><creatorcontrib>Davenport, Ian R</creatorcontrib><creatorcontrib>Nguyen, Thu A</creatorcontrib><creatorcontrib>Parker-Lemieux, KiTani</creatorcontrib><creatorcontrib>Payton-Stewart, Florastina</creatorcontrib><creatorcontrib>Williams, Christopher C</creatorcontrib><creatorcontrib>Boué, Stephen M</creatorcontrib><creatorcontrib>Burow, Matthew E</creatorcontrib><creatorcontrib>Collins-Burow, Bridgette</creatorcontrib><creatorcontrib>Hilliard, Aaron</creatorcontrib><creatorcontrib>Davidson, A Michael</creatorcontrib><creatorcontrib>Tilghman, Syreeta L</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</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>MEDLINE - 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A better understanding of this process is critical towards designing novel strategies for disease management. Previously, we demonstrated a global proteomic signature of letrozole-resistance associated with hormone-independence, enhanced cell motility and implications of epithelial mesenchymal transition (EMT). Letrozole-resistant breast cancer cells (LTLT-Ca) were treated with a novel phytoalexin, glyceollin I, and exhibited morphological characteristics synonymous with an epithelial phenotype and decreased proliferation. Letrozole-resistance increased Zinc Finger E-Box Binding Homeobox 1 (ZEB1) expression (4.51-fold), while glyceollin I treatment caused a -3.39-fold reduction. Immunofluorescence analyses resulted of glyceollin I-induced increase and decrease in E-cadherin and ZEB1, respectively. In vivo studies performed in ovariectomized, female nude mice indicated that glyceollin treated tumors stained weakly for ZEB1 and N-cadherin and strongly for E-cadherin. Compared to letrozole-sensitive cells, LTLT-Ca cells displayed enhanced motility, however in the presence of glyceollin I, exhibited a 68% and 83% decrease in invasion and migration, respectively. These effects of glyceollin I were mediated in part by inhibition of ZEB1, thus indicating therapeutic potential of glyceollin I in targeting EMT in letrozole resistant breast cancer.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>26703648</pmid><doi>10.3390/ijerph13010010</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antineoplastic Agents - metabolism Antineoplastic Agents - therapeutic use Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - physiopathology Cell Line, Tumor - drug effects Cell Movement Drug Resistance, Neoplasm - drug effects Epithelial-Mesenchymal Transition - drug effects Female Fluorescence Genotype & phenotype Humans Metastasis Mice Mice, Nude Nitriles - metabolism Nitriles - therapeutic use Pterocarpans - metabolism Transcription Factors - metabolism Triazoles - metabolism Triazoles - therapeutic use |
| title | Glyceollin I Reverses Epithelial to Mesenchymal Transition in Letrozole Resistant Breast Cancer through ZEB1 |
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