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Np63 activates EGFR signaling to induce loss of adhesion in triple-negative basal-like breast cancer cells
Purpose The basal-A subtype of triple-negative breast cancer is characterized by high levels of [DELTA]Np63. Various functions have been proposed for p63 in breast cancer initiation and growth, and p63 mediates chemotherapeutic response in a subset of triple-negative breast cancers. We investigated...
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Published in: | Breast cancer research and treatment 2017-06, Vol.163 (3), p.475 |
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creator | Holcakova, Jitka Nekulova, Marta Orzol, Paulina Nenutil, Rudolf Podhorec, Jan Svoboda, Marek Dvorakova, Petra |
description | Purpose The basal-A subtype of triple-negative breast cancer is characterized by high levels of [DELTA]Np63. Various functions have been proposed for p63 in breast cancer initiation and growth, and p63 mediates chemotherapeutic response in a subset of triple-negative breast cancers. We investigated the signaling pathways that are controlled by [DELTA]Np63 in basal-A triple-negative breast cancer. Methods Human basal-A triple-negative breast cancer cell lines with [DELTA]Np63[alpha] induction or inhibition were studied, along with primary human triple-negative breast cancer tissues. Proteomic, phospho-kinase array, mRNA measurements, and immunohistochemistry were employed. Results Global phosphoproteomics identified increased EGFR phosphorylation in MDA-MB-468 cells expressing [DELTA]Np63[alpha]. [DELTA]Np63[alpha] expression increased EGFR mRNA, total EGFR protein, and phospho-EGFR(Y1086), whereas silencing endogenous [DELTA]Np63 in HCC1806 cells reduced both total and phospho-EGFR levels and inhibited the ability of EGF to activate EGFR. EGFR pathway gene expression analysis indicated that [DELTA]Np63 alters EGFR-regulated genes involved in cell adhesion, migration, and angiogenesis. Addition of EGF or neutralizing EGFR antibodies demonstrated that EGFR activation is responsible for [DELTA]Np63-mediated loss of cellular adhesion. Finally, immunohistochemical staining showed that p63-positive triple-negative breast cancers were more likely to express high levels of EGFR than p63-negative cancers, corroborated by in silico analysis of gene expression profiling data. Conclusions These data identify EGFR as a major target for [DELTA]Np63 regulation that influences cancer cell adhesion in basal-like triple-negative breast cancer. |
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Various functions have been proposed for p63 in breast cancer initiation and growth, and p63 mediates chemotherapeutic response in a subset of triple-negative breast cancers. We investigated the signaling pathways that are controlled by [DELTA]Np63 in basal-A triple-negative breast cancer. Methods Human basal-A triple-negative breast cancer cell lines with [DELTA]Np63[alpha] induction or inhibition were studied, along with primary human triple-negative breast cancer tissues. Proteomic, phospho-kinase array, mRNA measurements, and immunohistochemistry were employed. Results Global phosphoproteomics identified increased EGFR phosphorylation in MDA-MB-468 cells expressing [DELTA]Np63[alpha]. [DELTA]Np63[alpha] expression increased EGFR mRNA, total EGFR protein, and phospho-EGFR(Y1086), whereas silencing endogenous [DELTA]Np63 in HCC1806 cells reduced both total and phospho-EGFR levels and inhibited the ability of EGF to activate EGFR. EGFR pathway gene expression analysis indicated that [DELTA]Np63 alters EGFR-regulated genes involved in cell adhesion, migration, and angiogenesis. Addition of EGF or neutralizing EGFR antibodies demonstrated that EGFR activation is responsible for [DELTA]Np63-mediated loss of cellular adhesion. Finally, immunohistochemical staining showed that p63-positive triple-negative breast cancers were more likely to express high levels of EGFR than p63-negative cancers, corroborated by in silico analysis of gene expression profiling data. Conclusions These data identify EGFR as a major target for [DELTA]Np63 regulation that influences cancer cell adhesion in basal-like triple-negative breast cancer.</description><identifier>ISSN: 0167-6806</identifier><identifier>EISSN: 1573-7217</identifier><identifier>DOI: 10.1007/s10549-017-4216-6</identifier><language>eng</language><publisher>Dordrecht: Springer</publisher><subject>Analysis ; Angiogenesis ; Antibodies ; Breast cancer ; Cancer research ; Cell adhesion ; Cell adhesion & migration ; Chemotherapy ; Epidermal growth factor receptors ; Epidermal growth factors ; Gene expression ; Immunohistochemistry ; Kinases ; Phosphorylation ; RNA ; Signal transduction ; Tumor cell lines</subject><ispartof>Breast cancer research and treatment, 2017-06, Vol.163 (3), p.475</ispartof><rights>COPYRIGHT 2017 Springer</rights><rights>Breast Cancer Research and Treatment is a copyright of Springer, 2017.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Holcakova, Jitka</creatorcontrib><creatorcontrib>Nekulova, Marta</creatorcontrib><creatorcontrib>Orzol, Paulina</creatorcontrib><creatorcontrib>Nenutil, Rudolf</creatorcontrib><creatorcontrib>Podhorec, Jan</creatorcontrib><creatorcontrib>Svoboda, Marek</creatorcontrib><creatorcontrib>Dvorakova, Petra</creatorcontrib><title>Np63 activates EGFR signaling to induce loss of adhesion in triple-negative basal-like breast cancer cells</title><title>Breast cancer research and treatment</title><description>Purpose The basal-A subtype of triple-negative breast cancer is characterized by high levels of [DELTA]Np63. Various functions have been proposed for p63 in breast cancer initiation and growth, and p63 mediates chemotherapeutic response in a subset of triple-negative breast cancers. We investigated the signaling pathways that are controlled by [DELTA]Np63 in basal-A triple-negative breast cancer. Methods Human basal-A triple-negative breast cancer cell lines with [DELTA]Np63[alpha] induction or inhibition were studied, along with primary human triple-negative breast cancer tissues. Proteomic, phospho-kinase array, mRNA measurements, and immunohistochemistry were employed. Results Global phosphoproteomics identified increased EGFR phosphorylation in MDA-MB-468 cells expressing [DELTA]Np63[alpha]. [DELTA]Np63[alpha] expression increased EGFR mRNA, total EGFR protein, and phospho-EGFR(Y1086), whereas silencing endogenous [DELTA]Np63 in HCC1806 cells reduced both total and phospho-EGFR levels and inhibited the ability of EGF to activate EGFR. EGFR pathway gene expression analysis indicated that [DELTA]Np63 alters EGFR-regulated genes involved in cell adhesion, migration, and angiogenesis. Addition of EGF or neutralizing EGFR antibodies demonstrated that EGFR activation is responsible for [DELTA]Np63-mediated loss of cellular adhesion. Finally, immunohistochemical staining showed that p63-positive triple-negative breast cancers were more likely to express high levels of EGFR than p63-negative cancers, corroborated by in silico analysis of gene expression profiling data. Conclusions These data identify EGFR as a major target for [DELTA]Np63 regulation that influences cancer cell adhesion in basal-like triple-negative breast cancer.</description><subject>Analysis</subject><subject>Angiogenesis</subject><subject>Antibodies</subject><subject>Breast cancer</subject><subject>Cancer research</subject><subject>Cell adhesion</subject><subject>Cell adhesion & migration</subject><subject>Chemotherapy</subject><subject>Epidermal growth factor receptors</subject><subject>Epidermal growth factors</subject><subject>Gene expression</subject><subject>Immunohistochemistry</subject><subject>Kinases</subject><subject>Phosphorylation</subject><subject>RNA</subject><subject>Signal transduction</subject><subject>Tumor cell lines</subject><issn>0167-6806</issn><issn>1573-7217</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNptUGFLwzAQDaLgnP4AvwUEv2UmTdukH8eYUxgKop9Lml67zKyZvczfb0DBCXJwdzzeO947Qq4FnwnO1R0KXuQV40KxPBMlK0_IRBRKMpUJdUomXJSKlZqX5-QCccs5rxSvJmT7tC8lNTa6TxMB6XJ1_0LR9YPxbuhpDNQN7cEC9QGRho6adgPowpBwGke398AG6E3SA20MGs-8e0_rCAYjtWawMFIL3uMlOeuMR7j6mVPydr98XTyw9fPqcTFfs15kpWSFSNayPK8aATZXmbYKoLK5zVueQ6WVLTLRNV0pBdcGTCartrNcN0qrttFWTsnN9939GD4OgLHehsOYAmEtdJViK13IX1ZvPNRu6EIcjd05tPW8SB6k5KlNyewfVqoWds6GATqX8D-C2yPBBoyPGwz-ENPL8Jj4BQVHgbs</recordid><startdate>20170601</startdate><enddate>20170601</enddate><creator>Holcakova, Jitka</creator><creator>Nekulova, Marta</creator><creator>Orzol, Paulina</creator><creator>Nenutil, Rudolf</creator><creator>Podhorec, Jan</creator><creator>Svoboda, Marek</creator><creator>Dvorakova, Petra</creator><general>Springer</general><general>Springer Nature B.V</general><scope>3V.</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>K9-</scope><scope>K9.</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope></search><sort><creationdate>20170601</creationdate><title>Np63 activates EGFR signaling to induce loss of adhesion in triple-negative basal-like breast cancer cells</title><author>Holcakova, Jitka ; Nekulova, Marta ; Orzol, Paulina ; Nenutil, Rudolf ; Podhorec, Jan ; Svoboda, Marek ; Dvorakova, Petra</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-g1263-510972449b1ec4728c7ee9c4c4d04e987c521fbf63108aea239dfc08b787db8c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Analysis</topic><topic>Angiogenesis</topic><topic>Antibodies</topic><topic>Breast cancer</topic><topic>Cancer research</topic><topic>Cell adhesion</topic><topic>Cell adhesion & migration</topic><topic>Chemotherapy</topic><topic>Epidermal growth factor receptors</topic><topic>Epidermal growth factors</topic><topic>Gene expression</topic><topic>Immunohistochemistry</topic><topic>Kinases</topic><topic>Phosphorylation</topic><topic>RNA</topic><topic>Signal transduction</topic><topic>Tumor cell lines</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Holcakova, Jitka</creatorcontrib><creatorcontrib>Nekulova, Marta</creatorcontrib><creatorcontrib>Orzol, Paulina</creatorcontrib><creatorcontrib>Nenutil, Rudolf</creatorcontrib><creatorcontrib>Podhorec, Jan</creatorcontrib><creatorcontrib>Svoboda, Marek</creatorcontrib><creatorcontrib>Dvorakova, Petra</creatorcontrib><collection>ProQuest Central (Corporate)</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest_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>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest_Research Library</collection><collection>Research Library (Corporate)</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>ProQuest Central Basic</collection><jtitle>Breast cancer research and treatment</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Holcakova, Jitka</au><au>Nekulova, Marta</au><au>Orzol, Paulina</au><au>Nenutil, Rudolf</au><au>Podhorec, Jan</au><au>Svoboda, Marek</au><au>Dvorakova, Petra</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Np63 activates EGFR signaling to induce loss of adhesion in triple-negative basal-like breast cancer cells</atitle><jtitle>Breast cancer research and treatment</jtitle><date>2017-06-01</date><risdate>2017</risdate><volume>163</volume><issue>3</issue><spage>475</spage><pages>475-</pages><issn>0167-6806</issn><eissn>1573-7217</eissn><abstract>Purpose The basal-A subtype of triple-negative breast cancer is characterized by high levels of [DELTA]Np63. Various functions have been proposed for p63 in breast cancer initiation and growth, and p63 mediates chemotherapeutic response in a subset of triple-negative breast cancers. We investigated the signaling pathways that are controlled by [DELTA]Np63 in basal-A triple-negative breast cancer. Methods Human basal-A triple-negative breast cancer cell lines with [DELTA]Np63[alpha] induction or inhibition were studied, along with primary human triple-negative breast cancer tissues. Proteomic, phospho-kinase array, mRNA measurements, and immunohistochemistry were employed. Results Global phosphoproteomics identified increased EGFR phosphorylation in MDA-MB-468 cells expressing [DELTA]Np63[alpha]. [DELTA]Np63[alpha] expression increased EGFR mRNA, total EGFR protein, and phospho-EGFR(Y1086), whereas silencing endogenous [DELTA]Np63 in HCC1806 cells reduced both total and phospho-EGFR levels and inhibited the ability of EGF to activate EGFR. EGFR pathway gene expression analysis indicated that [DELTA]Np63 alters EGFR-regulated genes involved in cell adhesion, migration, and angiogenesis. Addition of EGF or neutralizing EGFR antibodies demonstrated that EGFR activation is responsible for [DELTA]Np63-mediated loss of cellular adhesion. Finally, immunohistochemical staining showed that p63-positive triple-negative breast cancers were more likely to express high levels of EGFR than p63-negative cancers, corroborated by in silico analysis of gene expression profiling data. Conclusions These data identify EGFR as a major target for [DELTA]Np63 regulation that influences cancer cell adhesion in basal-like triple-negative breast cancer.</abstract><cop>Dordrecht</cop><pub>Springer</pub><doi>10.1007/s10549-017-4216-6</doi></addata></record> |
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subjects | Analysis Angiogenesis Antibodies Breast cancer Cancer research Cell adhesion Cell adhesion & migration Chemotherapy Epidermal growth factor receptors Epidermal growth factors Gene expression Immunohistochemistry Kinases Phosphorylation RNA Signal transduction Tumor cell lines |
title | Np63 activates EGFR signaling to induce loss of adhesion in triple-negative basal-like breast cancer cells |
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