LRP1 B is a novel member of the low-density lipoprotein receptor (LDLR) family. It was discovered as a putative tumor suppressor and is frequently deleted in lung cancer cells. It shares high sequence and structural homology with another giant member of the LDLR family, LRP. Receptors in the LDLR family mediate endocytosis of a variety of extracellular and membrane ligands and participate in signaling pathways that function in cell migration and differentiation. In addition, several receptors in the family regulate endocytosis and regeneration of urokinase plasminogen activator receptor (uPAR), which plays essential roles in the cell migration and invasion of cancer cells. LRP1 B and LRP have overlapping ligand binding specificities; however, our recent studies demonstrate that LRP1 B exhibits a significantly slower rate of endocytosis when compared to LRP. As a result, expression of LRP1 B prevents the regeneration of uPAR to the cell surface and inhibits cell migration. From these studies, we hypothesize that the tumor suppressive function of LRP1B is related to its ability to retain uPAR in a non-functional state on the cell surface, and that alterations in the expression and endocytic efficiency of LRP1B may impact the level of functional cell surface uPAR, tumor cell migration, invasion, growth, and metastasis. For the current proposal, we have designed experiments to dissect the mechanisms by which LRP1B suppresses uPAR function and to examine how changes in LRP1B expression and endocytosis influence cancer cell migration and tumor growth. We propose the following specific aims: 1) define interactions between LRP1B and the components of the uPAR system, and explore the roles of LRP1B in uPAR/integrin-mediated signaling; 2) dissect the mechanism underlying the slow endocytosis rate of LRP1 B; 3) examine the roles of LRP1B in uPAR-mediated human cancer cell proliferation, migration, and invasion in vitro, and tumorigenesis and metastasis in vivo; and 4) determine whether the LRPIB gene, transcript, and protein levels are altered in human tumor tissues. Results from these proposed studies should allow us to better understand if and how modulation of LRP1B expression in cancer cells influences uPAR-mediated tumor cell behavior. Together, these studies should allow us to vigorously test whether LRP1B is a tumor suppressor, and may provide a framework for the design of therapeutic strategies targeting LRP1B expression and function in human cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Ault, Grace S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Liu, Chia-Chen; Prior, Julie; Piwnica-Worms, David et al. (2010) LRP6 overexpression defines a class of breast cancer subtype and is a target for therapy. Proc Natl Acad Sci U S A 107:5136-41
Zhang, J; Li, Y; Liu, Q et al. (2010) Wnt signaling activation and mammary gland hyperplasia in MMTV-LRP6 transgenic mice: implication for breast cancer tumorigenesis. Oncogene 29:539-49
Song, Heesang; Li, Yonghe; Lee, Jiyeon et al. (2009) Low-density lipoprotein receptor-related protein 1 promotes cancer cell migration and invasion by inducing the expression of matrix metalloproteinases 2 and 9. Cancer Res 69:879-86
Liu, Chia-Chen; Pearson, Chelsea; Bu, Guojun (2009) Cooperative folding and ligand-binding properties of LRP6 beta-propeller domains. J Biol Chem 284:15299-307
Bu, Guojun; Lu, Wenyan; Liu, Chia-Chen et al. (2008) Breast cancer-derived Dickkopf1 inhibits osteoblast differentiation and osteoprotegerin expression: implication for breast cancer osteolytic bone metastases. Int J Cancer 123:1034-42
Knisely, Jane M; Li, Yonghe; Griffith, Janice M et al. (2007) Slow endocytosis of the LDL receptor-related protein 1B: implications for a novel cytoplasmic tail conformation. Exp Cell Res 313:3298-307
Chen, Sen; Bu, Guojun; Takei, Yoshifumi et al. (2007) Midkine and LDL-receptor-related protein 1 contribute to the anchorage-independent cell growth of cancer cells. J Cell Sci 120:4009-15
Li, Yonghe; Lu, Wenyan; Bu, Guojun (2005) Striking differences of LDL receptor-related protein 1B expression in mouse and human. Biochem Biophys Res Commun 333:868-73