The role of histamine in human mammary carcinogenesis: H3 and H4 receptors as potential therapeutic targets for breast cancer treatment.
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 demonstrate 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.
Medina
Vanina
V
Radioisotopes Laboratory, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
Croci
Máximo
M
Crescenti
Ernesto
E
Mohamad
Nora
N
Sanchez-Jiménez
Francisca
F
Massari
Noelia
N
Nuñez
Mariel
M
Cricco
Graciela
G
Martin
Gabriela
G
Bergoc
Rosa
R
Rivera
Elena
E
D000328:Adult; D000368:Aged; D001940:Breast / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy / Q000209:etiology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006632:Histamine / Q000032:analysis / Q000502:physiology*; D006640:Histidine Decarboxylase / Q000032:analysis; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008875:Middle Aged; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D043562:Receptors, G-Protein-Coupled / Q000032:analysis / Q000187:drug effects / Q000502:physiology*; D011968:Receptors, Histamine / Q000032:analysis / Q000187:drug effects / Q000502:physiology*; D018100:Receptors, Histamine H3 / Q000032:analysis / Q000187:drug effects / Q000502:physiology*; D000074040:Receptors, Histamine H4; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
C418607:HRH4 protein, human; D007093:Imidazoles; D018809:Proliferating Cell Nuclear Antigen; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D000074040:Receptors, Histamine H4; D006632:Histamine; D006640:Histidine Decarboxylase; D013890:Thiourea; C086108:clobenpropit