PUBLICATION
Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells
- Authors
- Vella, V., Giuliano, M., La Ferlita, A., Pellegrino, M., Gaudenzi, G., Alaimo, S., Massimino, M., Pulvirenti, A., Dicitore, A., Vigneri, P., Vitale, G., Malaguarnera, R., Morrione, A., Sims, A.H., Ferro, A., Maggiolini, M., Lappano, R., De Francesco, E.M., Belfiore, A.
- ID
- ZDB-PUB-211217-1
- Date
- 2021
- Source
- Cells 10(11): (Journal)
- Registered Authors
- Keywords
- IGF axis, breast cancer, hyperinsulinemia, insulin receptor isoform A, insulin receptor isoform transcriptome, insulin receptor isoforms, triple negative breast cancer, tumor promotion
- MeSH Terms
-
- Animals
- Carcinogenesis/metabolism*
- Carcinogenesis/pathology*
- Cell Line, Tumor
- Cell Movement/genetics
- Cell Proliferation/genetics
- Databases, Genetic
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Mice
- Neoplasm Invasiveness
- Neoplasm Metastasis
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/pathology
- Protein Isoforms/genetics
- Protein Isoforms/metabolism
- RNA-Seq
- Receptor, Insulin/genetics
- Receptor, Insulin/metabolism*
- Survival Analysis
- Transcriptome/genetics
- Triple Negative Breast Neoplasms/blood supply
- Triple Negative Breast Neoplasms/genetics
- Triple Negative Breast Neoplasms/metabolism*
- Triple Negative Breast Neoplasms/pathology*
- Zebrafish
- PubMed
- 34831367 Full text @ Cells
Citation
Vella, V., Giuliano, M., La Ferlita, A., Pellegrino, M., Gaudenzi, G., Alaimo, S., Massimino, M., Pulvirenti, A., Dicitore, A., Vigneri, P., Vitale, G., Malaguarnera, R., Morrione, A., Sims, A.H., Ferro, A., Maggiolini, M., Lappano, R., De Francesco, E.M., Belfiore, A. (2021) Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells. Cells. 10(11):.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping