Cargando…

Sprouty4 negatively regulates ERK/MAPK signaling and the transition from in situ to invasive breast ductal carcinoma

Breast ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal carcinoma (IDC). It is still unclear which DCIS will become invasive and which will remain indolent. Patients often receive surgery and radiotherapy, but this early intervention has not produced substantial decreas...

Descripción completa

Detalles Bibliográficos
Autores principales: Brock, Ethan J., Jackson, Ryan M., Boerner, Julie L., Li, Quanwen, Tennis, Meredith A., Sloane, Bonnie F., Mattingly, Raymond R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162601/
https://www.ncbi.nlm.nih.gov/pubmed/34048471
http://dx.doi.org/10.1371/journal.pone.0252314
_version_ 1783700750676787200
author Brock, Ethan J.
Jackson, Ryan M.
Boerner, Julie L.
Li, Quanwen
Tennis, Meredith A.
Sloane, Bonnie F.
Mattingly, Raymond R.
author_facet Brock, Ethan J.
Jackson, Ryan M.
Boerner, Julie L.
Li, Quanwen
Tennis, Meredith A.
Sloane, Bonnie F.
Mattingly, Raymond R.
author_sort Brock, Ethan J.
collection PubMed
description Breast ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal carcinoma (IDC). It is still unclear which DCIS will become invasive and which will remain indolent. Patients often receive surgery and radiotherapy, but this early intervention has not produced substantial decreases in late-stage disease. Sprouty proteins are important regulators of ERK/MAPK signaling and have been studied in various cancers. We hypothesized that Sprouty4 is an endogenous inhibitor of ERK/MAPK signaling and that its loss/reduced expression is a mechanism by which DCIS lesions progress toward IDC, including triple-negative disease. Using immunohistochemistry, we found reduced Sprouty4 expression in IDC patient samples compared to DCIS, and that ERK/MAPK phosphorylation had an inverse relationship to Sprouty4 expression. These observations were reproduced using a 3D culture model of disease progression. Knockdown of Sprouty4 in MCF10.DCIS cells increased ERK/MAPK phosphorylation as well as their invasive capability, while overexpression of Sprouty4 in MCF10.CA1d IDC cells reduced ERK/MAPK phosphorylation, invasion, and the aggressive phenotype exhibited by these cells. Immunofluorescence experiments revealed reorganization of the actin cytoskeleton and relocation of E-cadherin back to the cell surface, consistent with the restoration of adherens junctions. To determine whether these effects were due to changes in ERK/MAPK signaling, MEK1/2 was pharmacologically inhibited in IDC cells. Nanomolar concentrations of MEK162/binimetinib restored an epithelial-like phenotype and reduced pericellular proteolysis, similar to Sprouty4 overexpression. From these data we conclude that Sprouty4 acts to control ERK/MAPK signaling in DCIS, thus limiting the progression of these premalignant breast lesions.
format Online
Article
Text
id pubmed-8162601
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-81626012021-06-10 Sprouty4 negatively regulates ERK/MAPK signaling and the transition from in situ to invasive breast ductal carcinoma Brock, Ethan J. Jackson, Ryan M. Boerner, Julie L. Li, Quanwen Tennis, Meredith A. Sloane, Bonnie F. Mattingly, Raymond R. PLoS One Research Article Breast ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal carcinoma (IDC). It is still unclear which DCIS will become invasive and which will remain indolent. Patients often receive surgery and radiotherapy, but this early intervention has not produced substantial decreases in late-stage disease. Sprouty proteins are important regulators of ERK/MAPK signaling and have been studied in various cancers. We hypothesized that Sprouty4 is an endogenous inhibitor of ERK/MAPK signaling and that its loss/reduced expression is a mechanism by which DCIS lesions progress toward IDC, including triple-negative disease. Using immunohistochemistry, we found reduced Sprouty4 expression in IDC patient samples compared to DCIS, and that ERK/MAPK phosphorylation had an inverse relationship to Sprouty4 expression. These observations were reproduced using a 3D culture model of disease progression. Knockdown of Sprouty4 in MCF10.DCIS cells increased ERK/MAPK phosphorylation as well as their invasive capability, while overexpression of Sprouty4 in MCF10.CA1d IDC cells reduced ERK/MAPK phosphorylation, invasion, and the aggressive phenotype exhibited by these cells. Immunofluorescence experiments revealed reorganization of the actin cytoskeleton and relocation of E-cadherin back to the cell surface, consistent with the restoration of adherens junctions. To determine whether these effects were due to changes in ERK/MAPK signaling, MEK1/2 was pharmacologically inhibited in IDC cells. Nanomolar concentrations of MEK162/binimetinib restored an epithelial-like phenotype and reduced pericellular proteolysis, similar to Sprouty4 overexpression. From these data we conclude that Sprouty4 acts to control ERK/MAPK signaling in DCIS, thus limiting the progression of these premalignant breast lesions. Public Library of Science 2021-05-28 /pmc/articles/PMC8162601/ /pubmed/34048471 http://dx.doi.org/10.1371/journal.pone.0252314 Text en © 2021 Brock et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Brock, Ethan J.
Jackson, Ryan M.
Boerner, Julie L.
Li, Quanwen
Tennis, Meredith A.
Sloane, Bonnie F.
Mattingly, Raymond R.
Sprouty4 negatively regulates ERK/MAPK signaling and the transition from in situ to invasive breast ductal carcinoma
title Sprouty4 negatively regulates ERK/MAPK signaling and the transition from in situ to invasive breast ductal carcinoma
title_full Sprouty4 negatively regulates ERK/MAPK signaling and the transition from in situ to invasive breast ductal carcinoma
title_fullStr Sprouty4 negatively regulates ERK/MAPK signaling and the transition from in situ to invasive breast ductal carcinoma
title_full_unstemmed Sprouty4 negatively regulates ERK/MAPK signaling and the transition from in situ to invasive breast ductal carcinoma
title_short Sprouty4 negatively regulates ERK/MAPK signaling and the transition from in situ to invasive breast ductal carcinoma
title_sort sprouty4 negatively regulates erk/mapk signaling and the transition from in situ to invasive breast ductal carcinoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162601/
https://www.ncbi.nlm.nih.gov/pubmed/34048471
http://dx.doi.org/10.1371/journal.pone.0252314
work_keys_str_mv AT brockethanj sprouty4negativelyregulateserkmapksignalingandthetransitionfrominsitutoinvasivebreastductalcarcinoma
AT jacksonryanm sprouty4negativelyregulateserkmapksignalingandthetransitionfrominsitutoinvasivebreastductalcarcinoma
AT boernerjuliel sprouty4negativelyregulateserkmapksignalingandthetransitionfrominsitutoinvasivebreastductalcarcinoma
AT liquanwen sprouty4negativelyregulateserkmapksignalingandthetransitionfrominsitutoinvasivebreastductalcarcinoma
AT tennismereditha sprouty4negativelyregulateserkmapksignalingandthetransitionfrominsitutoinvasivebreastductalcarcinoma
AT sloanebonnief sprouty4negativelyregulateserkmapksignalingandthetransitionfrominsitutoinvasivebreastductalcarcinoma
AT mattinglyraymondr sprouty4negativelyregulateserkmapksignalingandthetransitionfrominsitutoinvasivebreastductalcarcinoma