title: Therapeutic potential of histamine H₄ receptor agonists in triple-negative human breast cancer experimental model.
abstract: OBJECTIVE
  The presence of the histamine H₄ receptor (H₄R) 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 H₄R ligands on the survival, tumour growth rate and metastatic capacity of breast cancer in an experimental model.
  
  
  METHODS
  Xenograft tumours of the highly invasive human breast cancer cell line MDA-MB-231 were established in immune deficient nude mice. The following H₄R agonists were employed: histamine (5 mg kg⁻¹), clozapine (1 mg kg⁻¹) and the experimental compound JNJ28610244 (10 mg kg⁻¹).
  
  
  RESULTS
  Data indicate that developed tumours were highly undifferentiated, expressed H₄R 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 H₄R 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
  Histamine through the H₄R exhibits a crucial role in tumour progression. Therefore, H₄R ligands offer a novel therapeutic potential as adjuvants for breast cancer treatment.
authors: Laboratory of Radioisotopes, School of Pharmacy and Biochemistry, University of Buenos Aires, Argentina.
authors: Diego J
authors: DJ
authors: Martinel Lamas
authors: Maximo
authors: M
authors: Croci
authors: Eliana
authors: E
authors: Carabajal
authors: Ernesto J V
authors: EJ
authors: Crescenti
authors: Lorena
authors: L
authors: Sambuco
authors: Noelia A
authors: NA
authors: Massari
authors: Rosa M
authors: RM
authors: Bergoc
authors: Elena S
authors: ES
authors: Rivera
authors: Vanina A
authors: VA
authors: Medina
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003024:Clozapine / Q000494:pharmacology; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006632:Histamine / Q000378:metabolism* / Q000494:pharmacology; D017442:Histamine Agonists / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D010091:Oximes / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D000074040:Receptors, Histamine H4; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
chemical_list: C418607:HRH4 protein, human; D017442:Histamine Agonists; D007211:Indoles; C000591334:JNJ28610244; D010091:Oximes; D018809:Proliferating Cell Nuclear Antigen; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D006632:Histamine; D003024:Clozapine
keywords: H4 receptor ligands; JNJ28610244; apoptosis; breast cancer; cell proliferation; clozapine; histamine