RESUMO
Luminal breast cancer (BrCa) has a favorable prognosis compared with other tumor subtypes. However, with time, tumors may evolve and lead to disease progression; thus, there is a great interest in unraveling the mechanisms that drive tumor metastasis and endocrine resistance. In this review, we focus on one of the many pathways that have been involved in tumor progression, the fibroblast growth factor/fibroblast growth factor receptor (FGFR) axis. We emphasize in data obtained from in vivo experimental models that we believe that in luminal BrCa, tumor growth relies in a crosstalk with the stromal tissue. We revisited the studies that illustrate the interaction between hormone receptors and FGFR. We also highlight the most frequent alterations found in BrCa cell lines and provide a short review on the trials that use FGFR inhibitors in combination with endocrine therapies. Analysis of these data suggests there are many players involved in this pathway that might be also targeted to decrease FGF signaling, in addition to specific FGFR inhibitors that may be exploited to increase their efficacy.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/fisiologia , Receptores de Fatores de Crescimento de Fibroblastos/fisiologia , Receptores de Esteroides/fisiologia , Transdução de Sinais/fisiologia , Animais , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/química , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Receptor alfa de Estrogênio/análise , Feminino , Fatores de Crescimento de Fibroblastos/genética , Amplificação de Genes , Humanos , Camundongos , Mutação , Receptor Cross-Talk/fisiologia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/genéticaRESUMO
BACKGROUND: Endocrine resistance and metastatic dissemination comprise major clinical challenges for breast cancer treatment. The fibroblast growth factor receptor family (FGFR) consists of four tyrosine kinase transmembrane receptors, involved in key biological processes. Genomic alterations in FGFR have been identified in advanced breast cancer and thus, FGFR are an attractive therapeutic target. However, the efficacy of FGFR inhibitors on in vivo tumor growth is still controversial. OBJECTIVE: The purpose of this study was to evaluate the role of FGFR in tumor growth and breast cancer progression. METHODS: Cell proliferation was assessed by 3H-thymidine uptake and cell counting in primary cultures of endocrine resistant mammary carcinomas and a human cell line, respectively. Tumor transplants and cell injections were used to determine in vivo growth and spontaneous metastasis. FGFR1-3 and αSMA expression were evaluated on primary tumors by immunohistochemistry. RESULTS: Antiprogestin resistant murine transplants and a human xenograft express high levels of total FGFR1-3. In vitro treatment with the FGFR inhibitor, BGJ398, impaired cell proliferation of resistant variants versus vehicle. In vivo, versus control, BGJ398 treatment decreased one out of four resistant tumors, however all tumors showed a decreased epithelial/stromal ratio. Finally, in a model of hormone resistant mammary cancer that spontaneously metastasizes to the lung, BGJ398 decreased the number of mice with lung metastasis. CONCLUSION: FGFR inhibitors are promising tools that require further investigation to identify sensitive tumors. These studies suggest that targeting FGFR combined with other targeted therapies will be useful to impair breast cancer progression.