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Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells

The insulin receptor isoform A (IR-A) plays an increasingly recognized role in fetal growth and tumor biology in response to circulating insulin and/or locally produced IGF2. This role seems not to be shared by the IR isoform B (IR-B). We aimed to dissect the specific impact of IR isoforms in modula...

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Autores principales: Vella, Veronica, Giuliano, Marika, La Ferlita, Alessandro, Pellegrino, Michele, Gaudenzi, Germano, Alaimo, Salvatore, Massimino, Michele, Pulvirenti, Alfredo, Dicitore, Alessandra, Vigneri, Paolo, Vitale, Giovanni, Malaguarnera, Roberta, Morrione, Andrea, Sims, Andrew H., Ferro, Alfredo, Maggiolini, Marcello, Lappano, Rosamaria, De Francesco, Ernestina Marianna, Belfiore, Antonino
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8621444/
https://www.ncbi.nlm.nih.gov/pubmed/34831367
http://dx.doi.org/10.3390/cells10113145
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author Vella, Veronica
Giuliano, Marika
La Ferlita, Alessandro
Pellegrino, Michele
Gaudenzi, Germano
Alaimo, Salvatore
Massimino, Michele
Pulvirenti, Alfredo
Dicitore, Alessandra
Vigneri, Paolo
Vitale, Giovanni
Malaguarnera, Roberta
Morrione, Andrea
Sims, Andrew H.
Ferro, Alfredo
Maggiolini, Marcello
Lappano, Rosamaria
De Francesco, Ernestina Marianna
Belfiore, Antonino
author_facet Vella, Veronica
Giuliano, Marika
La Ferlita, Alessandro
Pellegrino, Michele
Gaudenzi, Germano
Alaimo, Salvatore
Massimino, Michele
Pulvirenti, Alfredo
Dicitore, Alessandra
Vigneri, Paolo
Vitale, Giovanni
Malaguarnera, Roberta
Morrione, Andrea
Sims, Andrew H.
Ferro, Alfredo
Maggiolini, Marcello
Lappano, Rosamaria
De Francesco, Ernestina Marianna
Belfiore, Antonino
author_sort Vella, Veronica
collection PubMed
description The insulin receptor isoform A (IR-A) plays an increasingly recognized role in fetal growth and tumor biology in response to circulating insulin and/or locally produced IGF2. This role seems not to be shared by the IR isoform B (IR-B). We aimed to dissect the specific impact of IR isoforms in modulating insulin signaling in triple negative breast cancer (TNBC) cells. We generated murine 4T1 TNBC cells deleted from the endogenous insulin receptor (INSR) gene and expressing comparable levels of either human IR-A or IR-B. We then measured IR isoform-specific in vitro and in vivo biological effects and transcriptome in response to insulin. Overall, the IR-A was more potent than the IR-B in mediating cell migration, invasion, and in vivo tumor growth. Transcriptome analysis showed that approximately 89% of insulin-stimulated transcripts depended solely on the expression of the specific isoform. Notably, in cells overexpressing IR-A, insulin strongly induced genes involved in tumor progression and immune evasion including chemokines and genes related to innate immunity. Conversely, in IR-B overexpressing cells, insulin predominantly induced the expression of genes primarily involved in the regulation of metabolic pathways and, to a lesser extent, tumor growth and angiogenesis.
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spelling pubmed-86214442021-11-27 Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells Vella, Veronica Giuliano, Marika La Ferlita, Alessandro Pellegrino, Michele Gaudenzi, Germano Alaimo, Salvatore Massimino, Michele Pulvirenti, Alfredo Dicitore, Alessandra Vigneri, Paolo Vitale, Giovanni Malaguarnera, Roberta Morrione, Andrea Sims, Andrew H. Ferro, Alfredo Maggiolini, Marcello Lappano, Rosamaria De Francesco, Ernestina Marianna Belfiore, Antonino Cells Article The insulin receptor isoform A (IR-A) plays an increasingly recognized role in fetal growth and tumor biology in response to circulating insulin and/or locally produced IGF2. This role seems not to be shared by the IR isoform B (IR-B). We aimed to dissect the specific impact of IR isoforms in modulating insulin signaling in triple negative breast cancer (TNBC) cells. We generated murine 4T1 TNBC cells deleted from the endogenous insulin receptor (INSR) gene and expressing comparable levels of either human IR-A or IR-B. We then measured IR isoform-specific in vitro and in vivo biological effects and transcriptome in response to insulin. Overall, the IR-A was more potent than the IR-B in mediating cell migration, invasion, and in vivo tumor growth. Transcriptome analysis showed that approximately 89% of insulin-stimulated transcripts depended solely on the expression of the specific isoform. Notably, in cells overexpressing IR-A, insulin strongly induced genes involved in tumor progression and immune evasion including chemokines and genes related to innate immunity. Conversely, in IR-B overexpressing cells, insulin predominantly induced the expression of genes primarily involved in the regulation of metabolic pathways and, to a lesser extent, tumor growth and angiogenesis. MDPI 2021-11-12 /pmc/articles/PMC8621444/ /pubmed/34831367 http://dx.doi.org/10.3390/cells10113145 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Vella, Veronica
Giuliano, Marika
La Ferlita, Alessandro
Pellegrino, Michele
Gaudenzi, Germano
Alaimo, Salvatore
Massimino, Michele
Pulvirenti, Alfredo
Dicitore, Alessandra
Vigneri, Paolo
Vitale, Giovanni
Malaguarnera, Roberta
Morrione, Andrea
Sims, Andrew H.
Ferro, Alfredo
Maggiolini, Marcello
Lappano, Rosamaria
De Francesco, Ernestina Marianna
Belfiore, Antonino
Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells
title Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells
title_full Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells
title_fullStr Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells
title_full_unstemmed Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells
title_short Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells
title_sort novel mechanisms of tumor promotion by the insulin receptor isoform a in triple-negative breast cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8621444/
https://www.ncbi.nlm.nih.gov/pubmed/34831367
http://dx.doi.org/10.3390/cells10113145
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