RESUMO
BACKGROUND: The aim of this work was to improve the knowledge of the role of histamine in breast cancer by assessing the therapeutic efficacy of histamine and histamine H4 receptor (H4R) ligands in a triple-negative breast cancer (TNBC) model developed in immunocompetent hosts. By using publicly available genomic data, we further investigated whether histidine decarboxylase (HDC) could be a potential biomarker. METHODS: Tumours of 4T1 TNBC cells were orthotopically established in BALB/c mice. Treatments employed (mg kg-1): histamine (1 and 5), JNJ28610244 (H4R agonist, 1 and 5) and JNJ7777120 (H4R antagonist, 10). RESULTS: Increased HDC gene expression is associated with better relapse-free and overall survival in breast cancer patients. Histamine treatment (5 mg kg-1) of 4T1 tumour-bearing mice reduced tumour growth and increased apoptosis. Although no immunomodulatory effects were observed in wild-type mice, significant correlations between tumour weight and cytotoxic lymphocyte infiltration were detected in H4R knockout mice. H4R agonist or antagonist differentially modulated tumour growth and immunity in 4T1 tumour-bearing mice. CONCLUSIONS: Histamine plays a complex role and stands out as a promising drug for TNBC treatment, which deserves to be tested in clinical settings. HDC expression level is associated with clinicopathological characteristics, suggesting a prognostic value in breast cancer.
Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Histidina Descarboxilase/metabolismo , Receptores Histamínicos H4/genética , Receptores Histamínicos H4/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Bases de Dados Factuais , Feminino , Histamina/farmacologia , Humanos , Indóis/farmacologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Oximas/farmacologia , Piperazinas/farmacologia , Prognóstico , Neoplasias de Mama Triplo Negativas/mortalidade , Carga Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Although the role of histamine H4 receptor (H4R) in immune cells is being extensively investigated, its immunomodulatory function in cancer is completely unknown. This study aimed to investigate the role of H4R in antitumour immunity in a model of triple-negative breast cancer. METHODS: We evaluated growth parameters, histological characteristics and the composition of tumour, splenic and tumour draining lymph node (TDLN) immune subsets, in a syngeneic model, developed orthotopically with 4T1 cells in H4R knockout (H4R-KO) and wild-type mice. RESULTS: Mice lacking H4R show reduced tumour size and weight, decreased number of lung metastases and percentage of CD4+ tumour-infiltrating T cells, while exhibiting increased infiltration of NK cells and CD19+ lymphocytes. Likewise, TDLN of H4R-KO mice show decreased CD4+ T cells and T regulatory cells (CD4+CD25+FoxP3+), and increased percentages of NK cells. Finally, H4R-deficient mice show decreased Tregs in spleens and non-draining lymph nodes, and a negative correlation between tumour weight and the percentages of CD4+, CD19+ and NK splenic cells, suggesting that H4R also regulates antitumour immunity at a systemic level. CONCLUSIONS: This is the first report that demonstrates the participation of H4R in antitumour immunity, suggesting that H4R could be a target for cancer treatment.