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.
The results of these experiments will reveal how IGF and insulin receptors cooperate with Wnt-mediated tumorigenesis in mouse models of triple negative breast cancer and reveal relevance of these interactions in human breast cancers. The knowledge obtained from these studies will provide new insights into mechanisms of mammary tumor initiation, tumor phenotype and metastasis and will inform therapeutics to treat breast cancers.
|Obr, Alison E; Kumar, Sushil; Chang, Yun-Juan et al. (2018) Insulin-like growth factor receptor signaling in breast tumor epithelium protects cells from endoplasmic reticulum stress and regulates the tumor microenvironment. Breast Cancer Res 20:138|
|Kumar, Sushil; Davra, Viralkumar; Obr, Alison E et al. (2017) Crk adaptor protein promotes PD-L1 expression, EMT and immune evasion in a murine model of triple-negative breast cancer. Oncoimmunology 7:e1376155|