The Role of Histamine in Human Mammary Carcinogenesis. H3 and H4 Receptors as Potential Therapeutic Targets for Breast Cancer Treatment.

MEDINA V; CROCCI, M; CRESCENTI E; MOHAMAD N; SANCHEZ-JIMÉNEZ F; MASSARI NA; NUÑEZ, M.A; CRICCO G; MARTIN, G.A; BERGOC R; RIVERA E

Cancer biology & therapy

Landes Bioscience

Lugar: United States; Año: 2008 vol. 7 p. 28 - 35

1538-4047

There is increasing evidence that describes a histamine role in normal and cancer cellproliferation. To better understand the importance of histamine in breast cancerdevelopment, the expression of histamine H3 (H3R) and H4 (H4R) receptors and theirassociation with proliferating cell nuclear antigen (PCNA), histidine decarboxylase (HDC)and histamine content were explored in mammary biopsies. Additionally, we investigatedwhether H3R and H4R were implicated in the biological responses triggered by histaminein MDA-MB-231 breast cancer cells. The expression levels of H3R, H4R, PCNA, HDC andhistamine content were determined by immunohistochemistry in 40 benign and malignantlesions. MDA-MB-231 cells proliferation (clonogenic assay and BrdU incorporation) andcell cycle distribution (flow cytometry) were evaluated upon treatment with histamine, H3Rand H4R agonists and antagonists. Apoptosis was determined by Annexin staining andTUNEL assay. Cell migration was assessed by transwell system. Results indicate thatH3R 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 nontumoralbreast tissue surrounding carcinomas revealed a lower H3R expressioncompared to the tumor cells. Only 13% (2/15) of the benign lesions expressed H4Rcompared to 44% (11/25) of the carcinomas. Interestingly, H3R expression was correlatedin carcinomas with the expression of HDC and PCNA (P<0.0001), and also histaminecontent (P=0.0229). Accordingly, histamine increased MDA-MB-231 cells proliferation andalso migration via H3R. In contrast, activation of H4R inhibited proliferation and this effectwas associated with an arrest in the G0/G1 phase of the cell cycle and an induction ofapoptosis. Present findings demonstrate the presence of H3R and H4R in humanmammary tissue and suggest that H3R may be involved in the regulation of breast cancergrowth and progression representing a novel molecular target for new therapeuticapproach.