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.
Highlights
Breast cancer (BC) accounts for approximately 25% of all cancers and 15% of all cancer deaths in women
To compare cells expressing either the isoform A (IR-A) or isoform B (IR-B) isoforms, we established 4T1 cell clones characterized by conditional overexpression of either hIR-A or hIR-B and depletion of the endogenous insulin receptor (INSR). 4T1 triple negative breast cancer (TNBC) cells were obtained from American Type Culture Collection (ATCC, Manassas, VA, USA) and engineered within the first 6 months of purchase
We found that insulin receptor (IR)-A overexpression in TNBC cells enhances in vitro and in vivo oncogenic features
Summary
Breast cancer (BC) accounts for approximately 25% of all cancers and 15% of all cancer deaths in women. Progression to metastatic spread and resistance to chemotherapeutic drugs are major factors involved in BC-related mortality [1]. Approximately 80% of BCs overexpress the insulin receptor (IR) [4]. While the IR-B is considered the major physiological mediator of insulin-dependent metabolic actions, the IR-A plays an increasingly recognized role in fetal growth and tumor biology [4]. It regulates several aspects of tumor progression, including metabolic reprogramming [7], cell invasion, metastasis, epithelial-to-mesenchymal transition (EMT), stem-like cell phenotype, and resistance to cancer therapies [4]. IR-A is not exclusively expressed in fetal and tumor cells
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