There is increasing evidence that describes a histamine role in normal and cancer cell proliferation. To better understand the importance of histamine in breast cancer development, the expression of histamine H3 (H3R) and H4 (H4R) receptors and their association with proliferating cell nuclear antigen (PCNA), histidine decarboxylase (HDC) and histamine content were explored in mammary biopsies. Additionally, we investigated whether H3R and

Histamine is a biogenic amine responsible for multiple biological actions including regulation of physiological functions of mammary gland. It has been postulated that histamine plays a critical role in proliferation of normal and cancer cells. To investigate the biological responses that histamine exerts in malignant cells derived from human mammary gland, we evaluated in MDA-MB-231 line the expression of histamine receptors, histamine intracellular content, the capacity of histamine to influence proliferation, cell cycle progression, differentiation and apoptosis. We also studied histamine involvement in cellular response to ionizing radiation. HBL-100 cells were used as control of non-tumorigenic breast cells. Proliferation and surviving fraction were assessed by clonogenic assay. Cell cycle progression and lipid accumulation were determined by flow cytometry while apoptosis was studied by Annexin V and DNA fragmentation assays. Both cell lines expressed the four histamine receptors subtypes as evaluated by western blot and RT-PCR analyses, and present endogenous histamine. Histamine regulated proliferation of cancer cells in a dose-dependent way and 10 microM histamine reduced significantly proliferation to 23% inducing cell cycle arrest in G(2)/M phase, differentiation by 26% and a significant increase in the number of apoptotic cells (p < 0.01). These responses were not observed in HBL-100 cells. Furthermore, 10 microM histamine exclusively enhanced the radiosensitivity of MDA-MB-231 cells. These results represent the first report about the expression of H3 and H4 receptors in human breast cells. In addition, we conclude that histamine exerts different effects on biological responses of normal and cancer breast cells representing a promising target for the development of more specific and less toxic cancer therapies.

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BACKGROUND AND PURPOSEThe 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. EXPERIMENTAL APPROACHXenograft 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 RESULTSData 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 Ϯ 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 Ϯ 1.2, P < 0.01 in histamine group; 15.1 Ϯ 1.1, P < 0.001 in clozapine group; 10.8 Ϯ 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 IMPLICATIONSHistamine through the H4R exhibits a crucial role in tumour progression. Therefore, H4R ligands offer a novel therapeutic potential as adjuvants for breast cancer treatment. LINKED ARTICLESThis article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 AbbreviationsBrdU, 5-bromo-2′-deoxyuridine; ER, oestrogen receptor; H1R, histamine receptor 1; H2R, histamine receptor 2; H3R, histamine receptor 3; H4R, histamine receptor 4; siRNA, small interfering RNA