Lgr4 in Breast Cancer Stem Cells
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Breast cancer is the most commonly diagnosed cancer among American women. G-protein coupled receptors (GPCR) comprise a huge family protein with almost 800 members. GPCRs sense molecules or other stimuli outside the cell, and activate intracellular signals. Consequently, a large proportion of modern drugs target these receptors. Lgr4 is a GPCR implicated in the development of multiple organs; in the mammary gland, it is expressed in the basal epithelial subpopulation and controls organ development by regulating stem cell activity through the wnt/β-catenin pathway. High breast tumor expression of Lgr4 correlated with a high risk of tumor relapse after chemokine therapy and an elevated risk of bone metastasis. We crossed mice bearing a gene trap cassette in the Lgr4 locus with several breast cancer mouse models such as MMTV-Wnt1 and MMTV-PyMT to study the consequences of Lgr4 expression ablation in breast cancer progression. We found that the absence of Lgr4 significantly delayed tumor progression in both MMTV-Wnt1 and MMTV-PyMT mouse models. Meanwhile, Lgr4 ablation led to diminished lung metastases in MMTV-PyMT tumors and several breast cancer cell lines. Further studies revealed that the repression of tumor progression and metastasis formation was due to a decreased cancer stem cell number in tumors with Lgr4 down-regulation, as well as blocking of epithelial-mesenchymal transition. Mechanistic studies suggested that Lgr4 is a master regulator which modulates multiple pathways (Wnt, EGFR, MMP) in breast cancer. Our findings clarify the role of Lgr4 in tumor progression and metastasis formation, and provide a potential therapeutic target in breast cancer treatment.
Zeng, Li (2014). Lgr4 in Breast Cancer Stem Cells. Doctoral dissertation, Texas A & M University. Available electronically from