Activation Versus Inhibition of IGF1R: A Dual Role in Breast Tumorigenesis

Bulatowicz, Joseph J.; Wood, Teresa L.

doi:10.3389/fendo.2022.911079

Cited by 6 publications

(8 citation statements)

References 61 publications

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“…Recently, we used the human METABRIC database to stratify low and high IGF1R expressing tumors with lymph node positivity, a readout of early-stage metastasis. These analyses revealed that lymph node positivity is ~20% higher in human breast tumors with low IGF1R expression versus those with high IGF1R expression ( 9 ). Our previous studies reported IGF1R expression levels in human tumors are inversely correlated with several key target genes that alter the tumor microenvironment ( 17 ).…”

Section: Resultsmentioning

confidence: 99%

“… Model for how Reduced IGF1R in Human Breast Tumors (left) and in Mouse Basal-Like Mammary Tumors results in Enhanced Metastasis. The overview panel (left) summarizes human breast cancer data showing inverse correlation between IGF1R expression and patient survival and lymph node positivity [see ( 9 , 17 )] and from METABRIC data analyses in the current manuscript showing low tumor IGF1R expression is correlated with gene expression indicating increased tumor cell invasion properties and cell cycle and decreased cell adhesion. Similar pathways were identified from scRNA-Seq of the tumors in the mouse models with reduced IGF1R signaling or expression.…”

Section: Discussionmentioning

confidence: 99%

“…For example, EGFR signaling promotes growth of primary mammary tumors but suppresses growth of lung metastatic tumors [for review, see ( 4 )]. In the case of the IGF1R, results from mouse models also support a dual function in primary tumor formation and metastasis suppression which may be due to differential actions on proliferation or differentiation depending on the tumor lineage [for review, see ( 9 )].…”

Section: Introductionmentioning

confidence: 99%

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Breast tumor IGF1R regulates cell adhesion and metastasis: alignment of mouse single cell and human breast cancer transcriptomics

Obr

Bulatowicz²,

Chang³

et al. 2022

Front. Oncol.

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IntroductionThe acquisition of a metastatic phenotype is the critical event that determines patient survival from breast cancer. Several receptor tyrosine kinases have functions both in promoting and inhibiting metastasis in breast tumors. Although the insulin-like growth factor 1 receptor (IGF1R) has been considered a target for inhibition in breast cancer, low levels of IGF1R expression are associated with worse overall patient survival.MethodsTo determine how reduced IGF1R impacts tumor phenotype in human breast cancers, we used weighted gene co-expression network analysis (WGCNA) of Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) patient data to identify gene modules associated with low IGF1R expression. We then compared these modules to single cell gene expression analyses and phenotypes of mouse mammary tumors with reduced IGF1R signaling or expression in a tumor model of triple negative breast cancer.ResultsWGCNA from METABRIC data revealed gene modules specific to cell cycle, adhesion, and immune cell signaling that were inversely correlated with IGF1R expression in human breast cancers. Integration of human patient data with single cell sequencing data from mouse tumors revealed similar pathways necessary for promoting metastasis in basal-like mammary tumors with reduced signaling or expression of IGF1R. Functional analyses revealed the basis for the enhanced metastatic phenotype including alterations in E- and P-cadherins.DiscussionHuman breast and mouse mammary tumors with reduced IGF1R are associated with upregulation of several pathways necessary for promoting metastasis supporting the conclusion that IGF1R normally helps maintain a metastasis suppressive tumor microenvironment. We further found that reduced IGF1R signaling in tumor epithelial cells dysregulates cadherin expression resulting in reduced cell adhesion.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Breast tumor IGF1R regulates cell adhesion and metastasis: alignment of mouse single cell and human breast cancer transcriptomics

Obr

Bulatowicz²,

Chang³

et al. 2022

Front. Oncol.

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“…In summary, we believe that the negative outcomes of recent clinical trials, despite the obvious disappointment, were critically analyzed and important lessons were learned (26,184,185). Among other possible causes, a retrospective evaluation points out at a fierce competition between pharma companies as one of the reasons that hampered the development of efficient IGF1R drugs.…”

Section: Concluding Remarks: Future Igf Research and The Clinicsmentioning

confidence: 99%

Hallmarks of cancer: The insulin-like growth factors perspective

Werner

LeRoith

2022

Front. Oncol.

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The identification of a series of attributes or hallmarks that are shared by virtually all cancer cells constitutes a true milestone in cancer research. The conceptualization of a catalogue of common genetic, molecular, biochemical and cellular events under a unifying Hallmarks of Cancer idea had a major impact in oncology. Furthermore, the fact that different types of cancer, ranging from pediatric tumors and leukemias to adult epithelial cancers, share a large number of fundamental traits reflects the universal nature of the biological events involved in oncogenesis. The dissection of a complex disease like cancer into a finite directory of hallmarks is of major basic and translational relevance. The role of insulin-like growth factor-1 (IGF1) as a progression/survival factor required for normal cell cycle transition has been firmly established. Similarly well characterized are the biochemical and cellular activities of IGF1 and IGF2 in the chain of events leading from a phenotypically normal cell to a diseased one harboring neoplastic traits, including growth factor independence, loss of cell-cell contact inhibition, chromosomal abnormalities, accumulation of mutations, activation of oncogenes, etc. The purpose of the present review is to provide an in-depth evaluation of the biology of IGF1 at the light of paradigms that emerge from analysis of cancer hallmarks. Given the fact that the IGF1 axis emerged in recent years as a promising therapeutic target, we believe that a careful exploration of this signaling system might be of critical importance on our ability to design and optimize cancer therapies.

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“…In mice, IGFs, IGFBPs, and IGF1R are expressed in the virgin and the developing mammary gland, and cell-specific expression patterns have been described for IGFBPs ( Wood et al, 2000 ). The permissive role of the IGF1R for normal development, duct branching, and alveologenesis of the mouse mammary gland has recently been reviewed in great detail ( Bulatowicz and Wood, 2022 ). While IGF1 is strictly regulated by GH, IGF2 appears to mediate the effects of prolactin during mammary gland development and therefore is required for ductal branching and alveologenesis ( Brisken et al, 2002 ; Hovey et al, 2003 ).…”

Section: Introductionmentioning

confidence: 99%