Abstract
Substantial data from clinical trials and epidemiological studies show promising results for use of statins in many cancers, including mammary carcinoma. Breast tumor primarily metastasizes to bone to form osteolytic lesions, causing severe pain and pathological fracture. Here, we report that simvastatin acts as an inhibitor of osteolysis in a mouse model of breast cancer skeletal metastasis of human mammary cancer cell MDA-MB-231, which expresses the mutant p53R280K. Simvastatin and lovastatin attenuated migration and invasion of MDA-MB-231 and BT-20 breast tumor cells in culture. Acquisition of phenotype to express the cancer stem cell marker, CD44, leads to invasive potential of the tumor cells. Interestingly, statins significantly decreased the expression of CD44 protein via a transcriptional mechanism. shRNA-mediated down-regulation of CD44 markedly reduced the migration and invasion of breast cancer cells in culture. We identified that in the MDA-MB-231 cells, simvastatin elevated the levels of mutated p53R280K, which was remarkably active as a transcription factor. shRNA-derived inhibition of mutant p53R280K augmented the expression of CD44, leading to increased migration and invasion. Finally, we demonstrate an inverse correlation between expression of p53 and CD44 in the tumors of mice that received simvastatin. Our results reveal a unique function of statins, which foster enhanced expression of mutant p53R280K to prevent breast cancer cell metastasis to bone.
Highlights
Substantial data from clinical trials and epidemiological studies show promising results for use of statins in many cancers, including mammary carcinoma
We identified that in the MDA-MB-231 cells, simvastatin elevated the levels of mutated p53R280K, which was remarkably active as a transcription factor. shRNAderived inhibition of mutant p53R280K augmented the expression of CD44, leading to increased migration and invasion
The osteolytic nature of breast cancer metastasis to bone results from complex interaction between breast tumor cells and surrounding bone marrow stroma, which leads to bone destruction and intense pain
Summary
Substantial data from clinical trials and epidemiological studies show promising results for use of statins in many cancers, including mammary carcinoma. We show that simvastatin markedly prevents human MDA-MB-231 breast cancer cell metastasis to bone and inhibits migration and invasion of these cells in vitro. Both simvastatin and lovastatin increased the expression of p53 mRNA and protein in BT-20 breast cancer cells (supplemental Fig. S9, A and B).
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