The urokinase receptor (uPAR) is a cell-signaling receptor and a negative prognostic indicator in human breast cancer. uPAR-initiated cell signaling contributes to increased cell proliferation, cell survival, migration, and metastasis. In this work we utilize a number of cell and molecular biology techniques to demonstrate for the first time the possible effects of uPAR on cancer initiation, uPA-independent cell-signaling, and endocrine therapy resistance in breast cancer. We show that uPAR signaling can induce cancer stem cell (CSC)-like properties in breast cancer cell, either concurrently or independently of epithelial-mesenchymal transition. Over- expression of uPAR in human MDA-MB-468 and MCF-7 breast cancer cells promote the emergence of cells with CD24⁻/ CD44⁺ phenotype, characteristics for cancer stem cells. In addition, uPAR expression further increases the abundance of integrin subunits [beta]1/CD29 and [alpha]6/CD49f, which are also associated with the stem cell phenotype. The cancer stem cell properties are also evident in vivo, when a small number of uPAR over-expressing cells are capable of forming tumors in mice. We further demonstrated the uPAR can signal independently of uPA to induce ERK activating downstream of both H-Ras and Rac1. The transition in uPAR signaling from uPA-dependent and transient to autonomous and sustained is reminiscent of the transformation in ErbB2/HER-2 signaling observed when this gene is amplified in breast cancer. Vitronectin was essential for this activation, which was sensitive to the EGFR tyrosine kinase inhibitors Erlotinib and Gefitinib. In addition uPAR over-expression conferred MCF-7 cells resistance to the estrogen receptor anatagonist, Tamoxifen. Tamoxifen treatment also induced uPAR expression in MCF-7 cells, suggesting an important role for uPAR in endocrine therapy resistance. These studies suggest that uPAR over-expression has effects on breast cancer initiation and may provide a pathway for escape from breast cancer targeting therapeutics. It indicates that its expression could be useful as a biomarker for breast cancer stem cell or for cells that could be potentially resistant to Tamoxifen treatment

Cancer cells condition macrophages and other inflammatory cells in the tumor microenvironment so that these cells are more permissive for cancer growth and metastasis. Conditioning of inflammatory cells reflects, at least in part, soluble mediators (such as transforming growth factor β and IL-4) that are released by cancer cells and alter the phenotype of cells of the innate immune system. Signaling pathways in cancer cells that potentiate this activity are incompletely understood. The urokinase receptor (uPAR) is a cell-signaling receptor known to promote cancer cell survival, proliferation, metastasis, and cancer stem cell-like properties. The present findings show that uPAR expression in diverse cancer cells, including breast cancer, pancreatic cancer, and glioblastoma cells, promotes the ability of these cells to condition co-cultured bone marrow-derived macrophages so that the macrophages express significantly increased levels of arginase 1, a biomarker of the alternatively activated M2 macrophage phenotype. Expression of transforming growth factor β was substantially increased in uPAR-expressing cancer cells via a mechanism that requires uPA-initiated cell signaling. uPAR also controlled expression of IL-4 in cancer cells via a mechanism that involves activation of ERK1/2. The ability of uPAR to induce expression of factors that condition macrophages in the tumor microenvironment may constitute an important mechanism by which uPAR promotes cancer progression.

Cancer cells condition macrophages and other inflammatory cells in the tumor microenvironment so that these cells are more permissive for cancer growth and metastasis. Conditioning of inflammatory cells reflects, at least in part, soluble mediators (such as transforming growth factor β and IL-4) that are released by cancer cells and alter the phenotype of cells of the innate immune system. Signaling pathways in cancer cells that potentiate this activity are incompletely understood. The urokinase receptor (uPAR) is a cell-signaling receptor known to promote cancer cell survival, proliferation, metastasis, and cancer stem cell-like properties. The present findings show that uPAR expression in diverse cancer cells, including breast cancer, pancreatic cancer, and glioblastoma cells, promotes the ability of these cells to condition co-cultured bone marrow-derived macrophages so that the macrophages express significantly increased levels of arginase 1, a biomarker of the alternatively activated M2 macrophage phenotype. Expression of transforming growth factor β was substantially increased in uPAR-expressing cancer cells via a mechanism that requires uPA-initiated cell signaling. uPAR also controlled expression of IL-4 in cancer cells via a mechanism that involves activation of ERK1/2. The ability of uPAR to induce expression of factors that condition macrophages in the tumor microenvironment may constitute an important mechanism by which uPAR promotes cancer progression.