Pathways that regulate basal and metastatic phenotypes in triple negative breast cancers

总结

Summary Triple negative breast cancers (TNBCs) represent 10-20% of breast tumors; 75% of these have a basal-like phenotype. However, the basal phenotype itself does not necessarily predict a metastatic phenotype. Thus, it is critical to develop a clear understanding of the pathways and molecules that control tumor phenotypes to more effectively treat patients with breast cancer and to identify biomarkers of aggressive, metastatic tumor profiles. The long-term goal of this research is to understand what regulates basal and metastatic phenotypes in TNBC. We have identified a tyrosine kinase signaling pathway that, when disrupted, augments a basal phenotype in a mouse model of TNBC and converts tumors from non-metastatic to metastatic. Our published data and new preliminary data support the relevance of this model in a subtype of human TNBCs and provide the basis for our hypothesis that the luminal and basal lineages have distinct functions in the phenotypes of TNBCs. The goal of the proposed studies is to define the cellular mechanisms and alterations in other signaling pathways responsible for these important changes in tumor phenotypes. Three specific aims are proposed to demonstrate that 1) luminal insulin-like growth factor receptor (IGF-1R) regulates luminal to basal cell conversion and tumor-initiating phenotype, 2) myoepithelial IGF-1R regulates a metastatic phenotype, and 3) expression of the IGF-1R is decreased in human TNBCs with high Wnt and EMT signatures. At the completion of the aims, we expect to have obtained critical information in how interactions between tyrosine kinase, self-renewal and inflammatory pathways regulate phenotypes in TNBC.