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Simvastatin prevents skeletal metastasis of breast cancer by an antagonistic interplay between p53 and CD44.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2011 Apr 01; Vol. 286 (13), pp. 11314-27. Date of Electronic Publication: 2011 Jan 03. - Publication Year :
- 2011
-
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.
- Subjects :
- Amino Acid Substitution
Animals
Anticholesteremic Agents pharmacology
Bone Neoplasms genetics
Bone Neoplasms metabolism
Bone Neoplasms secondary
Breast Neoplasms genetics
Breast Neoplasms metabolism
Breast Neoplasms pathology
Cell Line, Tumor
Cell Movement drug effects
Cell Movement genetics
Female
Gene Expression Regulation, Neoplastic drug effects
Gene Expression Regulation, Neoplastic genetics
Humans
Hyaluronan Receptors genetics
Mice
Mice, Nude
Mutation, Missense
Neoplasm Invasiveness genetics
Neoplasm Invasiveness pathology
Neoplasm Invasiveness prevention & control
Neoplasm Metastasis drug therapy
Neoplasm Metastasis pathology
Neoplasm Transplantation
Osteolysis genetics
Osteolysis metabolism
Osteolysis pathology
Osteolysis prevention & control
Transcription, Genetic drug effects
Transcription, Genetic genetics
Transplantation, Heterologous
Tumor Suppressor Protein p53 genetics
Antineoplastic Agents pharmacology
Bone Neoplasms prevention & control
Breast Neoplasms drug therapy
Hyaluronan Receptors biosynthesis
Simvastatin pharmacology
Tumor Suppressor Protein p53 biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 286
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 21199873
- Full Text :
- https://doi.org/10.1074/jbc.M110.193714