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Breast tumor IGF1R regulates cell adhesion and metastasis: alignment of mouse single cell and human breast cancer
Alison E Obr1, Joseph J Bulatowicz1, Yun-Juan Chang2
1Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ, United States.
Introduction:
The 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.
Methods:
To 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.
Results:
WGCNA 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.
Discussion:
Human 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.
Insights
Reduced insulin-like growth factor 1 receptor (IGF1R) expression in breast cancer promotes metastasis by altering cell adhesion pathways. This suggests IGF1R helps maintain a metastasis-suppressive tumor microenvironment.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Metastasis is a critical determinant of breast cancer patient survival.
- Receptor tyrosine kinases play complex roles in breast tumor metastasis.
- Insulin-like growth factor 1 receptor (IGF1R) is a potential therapeutic target, yet low expression correlates with poor survival.
Purpose of the Study:
- To investigate the impact of reduced IGF1R expression on breast cancer metastasis.
- To identify molecular pathways associated with low IGF1R in human breast cancers.
- To compare findings with experimental models of reduced IGF1R signaling.
Main Methods:
- Weighted gene co-expression network analysis (WGCNA) of METABRIC patient data.
- Identification of gene modules correlated with IGF1R expression.
- Integration with single-cell gene expression data from mouse models of triple-negative breast cancer.
Main Results:
- Gene modules related to cell cycle, adhesion, and immune signaling inversely correlated with IGF1R expression.
- Similar metastatic pathways were identified in human and mouse models with reduced IGF1R.
- Alterations in E- and P-cadherin expression were linked to enhanced metastatic phenotype.
Conclusions:
- Reduced IGF1R in breast and mammary tumors is associated with pathways promoting metastasis.
- IGF1R appears to maintain a metastasis-suppressive tumor microenvironment.
- Decreased IGF1R signaling dysregulates cadherin expression, reducing cell adhesion and promoting metastasis.
