RESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/prevenção & controle , Neoplasias da Mama/tratamento farmacológico , Receptores de Hialuronatos/biossíntese , Sinvastatina/farmacologia , Proteína Supressora de Tumor p53/biossíntese , Substituição de Aminoácidos , Animais , Anticolesterolemiantes/farmacologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Receptores de Hialuronatos/genética , Camundongos , Camundongos Nus , Mutação de Sentido Incorreto , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/patologia , Transplante de Neoplasias , Osteólise/genética , Osteólise/metabolismo , Osteólise/patologia , Osteólise/prevenção & controle , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/genética , Transplante Heterólogo , Proteína Supressora de Tumor p53/genéticaRESUMO
The data derived from epidemiological and animal models confirm a beneficial effect of fish oil (rich in ω-3 polyunsaturated fatty acids) in the amelioration of tumor growth and progression, including breast cancer. The breast cancer patients often develop bone metastasis evidenced by osteolytic lesions, leading to severe pain and bone fracture. Using a mouse model of MDA-MB-231 human breast cancer cell metastasis to bone, here we show that fish oil diet enriched in DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) prevents the formation of osteolytic lesions in bone, indicating suppression of cancer cell metastasis to bone. These results are supported by our data showing both DHA and EPA significantly attenuate the migration/invasion of MDA-MB-231 breast cancer cells in culture. The mechanism that limits breast cancer cells to selective metastasis to bone remains hitherto unexplored. Aberrant increased expression of CD44 is associated with generation of cancer stem cells, which contribute to metastasis of breast cancer cells. We demonstrate that DHA and EPA significantly inhibit the expression of CD44 protein and mRNA by a transcriptional mechanism. Furthermore, we show markedly reduced levels of CD44 mRNA and protein in the tumors of mice, which were fed fish oil diet than those in control diet. Our data provide the first evidence for a salutary effect of fish oil on breast cancer metastasis to bone. Our results identify a novel function of the fish oil active components, DHA and EPA, which target the cell-intrinsic pro-metastatic molecule CD44 to inhibit migration/invasion.
Assuntos
Neoplasias Ósseas/prevenção & controle , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/uso terapêutico , Óleos de Peixe/uso terapêutico , Receptores de Hialuronatos/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Dieta , Feminino , Humanos , Receptores de Hialuronatos/genética , Camundongos , Metástase Neoplásica , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We report the case of a 63-year-old woman who suffered from mixed connective tissue disease (MCTD) complicated with thymic carcinoma and Hashimoto's thyroiditis. Although many systemic syndromes associated with thymoma and thymic carcinoma, i.e., myasthenia gravis, pure red cell aplasia, hypogammaglobulinemia, and Hashimoto's thyroiditis, are known, this is the first report of MCTD complicated with thymic carcinoma. It was suggested that MCTD may be a paraneoplastic syndrome associated with thymic carcinoma.
