The role of histamine in human mammary carcinogenesis (original) (raw)
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Cancer Biology & Therapy, 2008
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 H4R were implicated in the biological responses triggered by histamine in MDA-MB-231 breast cancer cells. The expression levels of H3R, H4R, PCNA, HDC and histamine content were determined by immunohistochemistry in 40 benign and malignant lesions. MDA-MB-231 cells proliferation (clonogenic assay and BrdU incorporation) and cell cycle distribution (flow cytometry) were evaluated upon treatment with histamine, H3R and H4R agonists and antagonists. Apoptosis was determined by Annexin staining and TUNEL assay. Cell migration was assessed by transwell system. Results indicate that H3R was detected in 67% (10/15) of benign lesions and in almost all carcinomas (24/25), being the level of its expression significantly higher in carcinomas (p = 0.0016). The non-tumoral breast tissue surrounding carcinomas revealed a lower H3R expression compared to the tumor cells. Only 13% (2/15) of the benign lesions expressed H4R compared to 44% (11/25) of the carcinomas. Interestingly, H3R expression was correlated in carcinomas with the expression of HDC and PCNA (p < 0.0001), and also histamine content (p = 0.0229). Accordingly, histamine increased MDA-MB-231 cells proliferation and also migration via H3R. In contrast, activation of H4R inhibited proliferation and this effect was associated with an arrest in the G 0 /G 1 phase of the cell cycle and an induction of apoptosis. Present findings demon-strate the presence of H3R and H4R in human mammary tissue and suggest that H3R may be involved in the regulation of breast cancer growth and progression representing a novel molecular target for new therapeutic approach.
Histamine-mediated signaling processes in human malignant mammary cells
Cancer Biology & Therapy, 2006
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 nontumorigenic 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 µM 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 µM 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.
H1 and H2 histamine receptors in human mammary carcinomas
Agents and Actions, 1993
We previously reported the presence of H a and H 2 histamine receptors in an experimental mammary carcinoma induced in rats. Experiments carried out in vivo and in vitro indicate that by acting on these receptors, histamine and antagonists modulate tumor growth. In the present study, binding experiments were performed with human breast cancer biopsies. All the tumors examined exhibited specific binding sites for histamine. Some of them showed the high and low affinity double site previously characterized in the experimental carcinoma. The high affinity site Kd = 18 +_ 6 nM, 50 _+ 33 fm/mg, exhibits H 2 binding characteristics while the low affinity one, Kd = 54__ 22 nM and 217 +_ 173 fm/mg, corresponds to an H a receptor. Approximately 30 % of the tumors studied were negative for H 2 receptors while all of them showed specific binding for [3H]-mepyramine. These data suggest that histamine may regulate cell growth in a high proportion of human mammary carcinomas, offering possibilities for new therapeutic alternatives.
Histamine H4 receptor: insights into a potential therapeutic target in breast cancer
Frontiers in bioscience (Scholar edition), 2015
Breast cancer is the second most common cancer worldwide, and the leading cause of cancer death in women. Several studies underlined the critical role of histamine in breast cancer development and progression. This review addresses the latest evidence regarding the involvement of histamine and histamine receptors in breast cancer, focusing particularly in the histamine H4 receptor (H4R). Histamine concentration in breast cancer tissues was found to be higher than that in normal tissues of healthy controls by means of an increase in the activity of histidine decarboxylase (HDC), the enzyme involved in histamine production. The expression of H4R in different experimental models and human biopsies, the associated biological responses, as well as the in vivo treatment of experimental tumors with H4R ligands is reviewed. Evidence demonstrates that the H4R exhibits a key role in histamine-mediated biological processes such as cell proliferation, senescence and apoptosis in breast cancer. ...
Histamine receptors and cancer pharmacology: Histamine receptors in cancer
British Journal of Pharmacology, 2010
Considerable evidence has been collected indicating that histamine can modulate proliferation of different normal and malignant cells. High histamine biosynthesis and content together with histamine receptors have been reported in different human neoplasias including melanoma, colon and breast cancer, as well as in experimental tumours in which histamine has been postulated to behave as an important paracrine and autocrine regulator of proliferation. The discovery of the human histamine H4 receptor in different tissues has contributed to our understanding of histamine role in numerous physiological and pathological conditions revealing novel functions for histamine and opening new perspectives in histamine pharmacology research. In the present review we aimed to briefly summarize current knowledge on histamine and histamine receptor involvement in cancer before focusing on some recent evidence supporting the novel role of histamine H4 receptor in cancer progression representing a promising molecular target and avenue for cancer drug development.LINKED ARTICLESBJP has previously published a Histamine themed issue (2009). To view this issue visit http://dx.doi.org/10.1111/bph.2009.157.issue-1
Histamine receptors and cancer pharmacology
British Journal of Pharmacology, 2010
Considerable evidence has been collected indicating that histamine can modulate proliferation of different normal and malignant cells. High histamine biosynthesis and content together with histamine receptors have been reported in different human neoplasias including melanoma, colon and breast cancer, as well as in experimental tumours in which histamine has been postulated to behave as an important paracrine and autocrine regulator of proliferation. The discovery of the human histamine H4 receptor in different tissues has contributed to our understanding of histamine role in numerous physiological and pathological conditions revealing novel functions for histamine and opening new perspectives in histamine pharmacology research. In the present review we aimed to briefly summarize current knowledge on histamine and histamine receptor involvement in cancer before focusing on some recent evidence supporting the novel role of histamine H4 receptor in cancer progression representing a promising molecular target and avenue for cancer drug development.
Study of the antitumour effects and the modulation of immune response by histamine in breast cancer
British Journal of Cancer
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 infi...
Immunomodulatory role of histamine H4 receptor in breast cancer
British journal of cancer, 2018
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. 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. 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 (CD4CD25FoxP3), and increased percentages of NK cells. Finally, H4R-deficient mice show decreased Tregs in spleens and non-draining lymph nodes, and a negative co...