UC San Diego

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