Therapeutic potential of histamine H₄ receptor agonists in triple-negative human breast cancer experimental model

The presence of the histamine H&sub4; receptor (H&sub4;R) was previously reported in benign and malignant lesions and cell lines derived from the human mammary gland. The aim of this work was to evaluate the effects of H&sub4;R ligands on the survival, tumour growth rate and metastatic capacity of breast cancer in an experimental model. Experimental approach: Xenograft tumours of the highly invasive human breast cancer cell line MDA-MB-231 were established in immune deficient nude mice. The following H&sub4;R agonists were employed: histamine (5 mg kg⁻¹), clozapine (1 mg kg⁻¹) and the experimental compound JNJ28610244 (10 mg kg⁻¹).

The presence of the histamine H&sub4; receptor (H&sub4;R) was previously reported in benign and malignant lesions and cell lines derived from the human mammary gland. The aim of this work was to evaluate the effects of H&sub4;R ligands on the survival, tumour growth rate and metastatic capacity of breast cancer in an experimental model. Experimental approach: Xenograft tumours of the highly invasive human breast cancer cell line MDA-MB-231 were established in immune deficient nude mice. The following H&sub4;R agonists were employed: histamine (5 mg kg⁻¹), clozapine (1 mg kg⁻¹) and the experimental compound JNJ28610244 (10 mg kg⁻¹).

Data indicate that developed tumours were highly undifferentiated, expressed H&sub4;R and exhibited high levels of histamine content and proliferation marker (PCNA) while displaying low apoptosis. Mice of the untreated group displayed a median survival of 60 days and a tumour doubling time of 7.4 ± 0.6 days. A significant decrease in tumour growth evidenced by an augment of the tumour doubling time was observed in the H&sub4;R agonist groups (13.1 ± 1.2, P < 0.01 in histamine group; 15.1 ± 1.1, P < 0.001 in clozapine group; 10.8 ± 0.7, P < 0.01 in JNJ28610244 group). This effect was associated with a decrease in the PCNA expression levels, and also reduced intratumoural vessels in histamine and clozapine treated mice. Histamine significantly increased median survival (78 days; Log rank Mantel-Cox Test, P = 0.0025; Gehan-Breslow-Wilcoxon Test, P = 0.0158) and tumoural apoptosis. Conclusions and implications: Histamine through the H&sub4;R exhibits a crucial role in tumour progression. Therefore, H&sub4;R ligands offer a novel therapeutic potential as adjuvants for breast cancer treatment.