title: Simvastatin prevents skeletal metastasis of breast cancer by an antagonistic interplay between p53 and CD44.
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.
authors.affiliation: Department of Pathology, University of Texas Health Science Center, San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Chandi Charan
authors.initials: CC
authors.lastname: Mandal
authors.forename: Nayana
authors.initials: N
authors.lastname: Ghosh-Choudhury
authors.forename: Toshi
authors.initials: T
authors.lastname: Yoneda
authors.forename: Goutam Ghosh
authors.initials: GG
authors.lastname: Choudhury
authors.forename: Nandini
authors.initials: N
authors.lastname: Ghosh-Choudhury
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D020125:Mutation, Missense; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000473:pathology; D009368:Neoplasm Transplantation; D010014:Osteolysis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D019821:Simvastatin / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000924:Anticholesteremic Agents; D000970:Antineoplastic Agents; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019821:Simvastatin