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:	Veronica Vella, Marika Giuliano, Alessandro La Ferlita, Michele Pellegrino, Germano Gaudenzi, Salvatore Alaimo, Michele Massimino, Alfredo Pulvirenti, Alessandra Dicitore, Paolo Vigneri, Giovanni Vitale, Roberta Malaguarnera, Andrea Morrione, Andrew H. Sims, Alfredo Ferro, Marcello Maggiolini, Rosamaria Lappano, Ernestina Marianna De Francesco, Antonino Belfiore
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	insulin receptor isoform A insulin receptor isoforms IGF axis breast cancer triple negative breast cancer insulin receptor isoform transcriptome Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/f6c5405a564f4ced8061b97fe65d34ed
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spelling	oai:doaj.org-article:f6c5405a564f4ced8061b97fe65d34ed2021-11-25T17:11:56ZNovel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells10.3390/cells101131452073-4409https://doaj.org/article/f6c5405a564f4ced8061b97fe65d34ed2021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3145https://doaj.org/toc/2073-4409The 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 (<i>INSR</i>) 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.Veronica VellaMarika GiulianoAlessandro La FerlitaMichele PellegrinoGermano GaudenziSalvatore AlaimoMichele MassiminoAlfredo PulvirentiAlessandra DicitorePaolo VigneriGiovanni VitaleRoberta MalaguarneraAndrea MorrioneAndrew H. SimsAlfredo FerroMarcello MaggioliniRosamaria LappanoErnestina Marianna De FrancescoAntonino BelfioreMDPI AGarticleinsulin receptor isoform Ainsulin receptor isoformsIGF axisbreast cancertriple negative breast cancerinsulin receptor isoform transcriptomeBiology (General)QH301-705.5ENCells, Vol 10, Iss 3145, p 3145 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	insulin receptor isoform A insulin receptor isoforms IGF axis breast cancer triple negative breast cancer insulin receptor isoform transcriptome Biology (General) QH301-705.5
spellingShingle	insulin receptor isoform A insulin receptor isoforms IGF axis breast cancer triple negative breast cancer insulin receptor isoform transcriptome Biology (General) QH301-705.5 Veronica Vella Marika Giuliano Alessandro La Ferlita Michele Pellegrino Germano Gaudenzi Salvatore Alaimo Michele Massimino Alfredo Pulvirenti Alessandra Dicitore Paolo Vigneri Giovanni Vitale Roberta Malaguarnera Andrea Morrione Andrew H. Sims Alfredo Ferro Marcello Maggiolini Rosamaria Lappano Ernestina Marianna De Francesco Antonino Belfiore Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells
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 (<i>INSR</i>) 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.
format	article
author	Veronica Vella Marika Giuliano Alessandro La Ferlita Michele Pellegrino Germano Gaudenzi Salvatore Alaimo Michele Massimino Alfredo Pulvirenti Alessandra Dicitore Paolo Vigneri Giovanni Vitale Roberta Malaguarnera Andrea Morrione Andrew H. Sims Alfredo Ferro Marcello Maggiolini Rosamaria Lappano Ernestina Marianna De Francesco Antonino Belfiore
author_facet	Veronica Vella Marika Giuliano Alessandro La Ferlita Michele Pellegrino Germano Gaudenzi Salvatore Alaimo Michele Massimino Alfredo Pulvirenti Alessandra Dicitore Paolo Vigneri Giovanni Vitale Roberta Malaguarnera Andrea Morrione Andrew H. Sims Alfredo Ferro Marcello Maggiolini Rosamaria Lappano Ernestina Marianna De Francesco Antonino Belfiore
author_sort	Veronica Vella
title	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_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_sort	novel mechanisms of tumor promotion by the insulin receptor isoform a in triple-negative breast cancer cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/f6c5405a564f4ced8061b97fe65d34ed
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Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells

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