LRPs and Tumorigenesis

The Wnt/beta-catenin signaling pathway is involved in tumorigenesis. Low-density lipoprotein receptor-related protein 6 (LRP6), a member of the low-density lipoprotein receptor (LDLR) family, is an indispensable element of the canonical Wnt/beta-catenin pathway as it interacts with several components of this signaling pathway.

Image representing LRP6 overexpressed in mice

When bound to ligand Wnt and cytosolic protein axin, LRP6 promotes Wnt/beta-catenin signaling. LRP6 is frequently upregulated in human malignant tissues. Recently, the lab found that when human LRP6 is overexpressed in mice, the animals' mammary glands exhibit significant hyperplasia, a precursor to breast cancer.1 In addition, LRP6 silencing in breast cancer cells reduces Wnt/beta-catenin signaling, cell proliferation and in vivo tumor growth. In vivo administration of an LRP6 antagonist, MESD, markedly suppressed tumor growth without causing undesirable side effects.2 The lab also demonstrated that the increased low-density lipoprotein receptor-related protein 1 (LRP1) expression in glioblastoma promotes tumor cell migration and invasion by upregulating the expression of several metalloproteases.3

For this research focus, Dr. Bu's lab aims to examine how modulation of LRP expression influences tumor development and progression in vitro and in vivo, and to test LRP antagonists as potential therapeutic agents.

References

  • Zhang J, Li Y, Liu Q, Lu W, Bu G. Wnt signaling activation and mammary gland hyperplasia in MMTV-LRP6 transgenic mice: implication for breast cancer tumorigenesis. Oncogene. 2010 Jan 28;29(4):539-49. PMID: 19881541
  • Liu CC, Prior J, Piwnica-Worms D, Bu G. LRP6 overexpression defines a class of breast cancer subtype and is a target for therapy. Proc Natl Acad Sci USA. 2010 Mar 16;107(11):5136-41. PMID: 20194742
  • Song H, Li Y, Lee J, Schwartz AL, Bu G. 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. 2009 Feb 1;69(3):879-86. PMID: 19176371