The current studies are a supplement to a proposal on what regulates basal and metastatic phenoytpes in triple negative breast cancer (TNBC) with a focus on the function of the insulin-like growth factor type 1 receptor (IGF-1R). The proposed supplementary research project will extend studies related to Aim 1 of the parent grant that were designed to investigate the interaction between the IGF-1R and the Wnt signaling pathway. Our recent analysis of the human breast cancer database revealed an inverse correlation Wnt2 and its receptor, Frizzled 9 (Fzd9), and IGF-1R expression. Moreover, in Wnt-driven mouse mammary tumors with reduced IGF-1R signaling leading to a metastatic phenotype, we also identified increased Wnt2 and Fzd9 expression. Wnt2 is the prominent Wnt ligand for Fzd9, and this signaling loop follows the canonical Wnt pathway wherein Wnt2 binding to Fzd9 increases the levels of total ?-catenin. Expression of Wnt2 and Fzd9 are elevated in several different kinds of cancer including breast, and Wnt2 promotes the development of a more invasive, metastatic cancer phenotype in breast and colorectal tumor cells. Our preliminary data further confirm that Fzd9 is upregulated in the human luminal epithelial MCF7 breast cancer cell line after inhibiting IGF-1R. Wnt2 expression has been reported in cancer-associated fibroblasts (CAFs); our preliminary data show that some human breast cancer cells also express Wnt2 in addition to Fzd9 suggesting this signaling loop can act in both a paracrine and autocrine manner. Taken together, the data provide the basis for our new hypothesis that reduced levels of IGF-1R in breast cancer leads to increased activation of the Wnt2/Fzd9 signaling loop. This will be tested by the following two specific aims: 1) Determine how the Wnt2/Fzd9 signaling axis is regulated by reduced IGF-1R signaling and define the cellular components responsible for Wnt2 expression. 2) Investigate how the Wnt2/Fzd9 signaling axis alters tumor cell phenotype in the context of reduced IGF-1R function.
The results of these experiments will reveal how IGF receptors cooperate with Wnt-mediated tumorigenesis in human breast cancer cells and in mouse models of triple negative breast cancer. The knowledge obtained from these studies will provide new insights into mechanisms of breast 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|