RESUMO
Although tamoxifen treatment is associated with improved survival in patients with estrogen receptor (ER)-positive breast tumors, resistance remains an important clinical obstacle. Signaling through growth factor signaling pathways, in particular through receptor tyrosine kinases, has been demonstrated to confer tamoxifen resistance in an estradiol-independent manner. The Ron receptor tyrosine kinase, a member of the c-Met family of receptors, is expressed in a number of human epithelial tumors, and elevated expression of Ron is associated with poor prognosis in women with breast cancer. In this report, we evaluated the role of Ron receptor activation in conferring resistance to tamoxifen in human and murine breast cancer cell lines. Activation of Ron by its ligand, hepatocyte growth factor-like protein (HGFL) was associated with partial rescue from tamoxifen-induced growth inhibition in Ron-expressing cell lines. Western analysis revealed that treatment of the T47D human breast cancer cell line with tamoxifen and HGFL was associated with increased phosphorylation of mitogen-activated protein kinase (MAPK) 1/2 and phosphorylation of serine residue 118 of ER. Expression of ER-dependent genes was increased in cells treated with tamoxifen and HGFL by quantitative reverse transcription-polymerase chain reaction. All of these effects were inhibited by treatment with either a Ron-neutralizing antibody or a MEK1 inhibitor, suggesting the specificity of the effect to Ron, and the involvement of the MAPK 1/2 signaling pathway. In summary, these results illustrate a novel connection between the Ron receptor tyrosine kinase and an important mechanism of tamoxifen resistance in breast cancer.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Carcinoma/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores Proteína Tirosina Quinases/agonistas , Tamoxifeno/uso terapêutico , Animais , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma/metabolismo , Carcinoma/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos/genética , Ativação Enzimática/efeitos dos fármacos , Feminino , Flavonoides/farmacologia , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Camundongos , Camundongos Transgênicos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/farmacologia , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , TransfecçãoRESUMO
Acute lung injury (ALI), a severe respiratory syndrome, develops in response to numerous insults and responds poorly to therapeutic intervention. Recently, cDNA microarray analyses were performed that indicated several pathogenic responses during nickel-induced ALI, including marked macrophage activation. Macrophage activation is mediated, in part, via the receptor tyrosine kinase Ron. To address the role of Ron in ALI, the response of mice deficient in the cytoplasmic domain of Ron (Ron tk-/-) were assessed in response to nickel exposure. Ron tk-/- mice succumb to nickel-induced ALI earlier, express larger, early increases in interleukin-6, monocyte chemoattractant protein-1, and macrophage inflammatory protein-2, display greater serum nitrite levels, and exhibit earlier onset of pulmonary pathology and augmented pulmonary tyrosine nitrosylation. Increases in cytokine expression and cellular nitration can lead to tissue damage and are consistent with the differences between genotypes in the early onset of pathology and mortality in Ron tk-/- mice. These analyses indicate a role for the tyrosine kinase receptor Ron in ALI.