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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
Main Authors: Holcakova, Jitka, Nekulova, Marta, Orzol, Paulina, Nenutil, Rudolf, Podhorec, Jan, Svoboda, Marek, Dvorakova, Petra
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container_issue 3
container_start_page 475
container_title Breast cancer research and treatment
container_volume 163
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 &amp; 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. 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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.</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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