Histamine and Breast Cancer: a New Role for a Well Known Amine

GRACIELA CRICCO; NORA MOHAMAD; MARIA SOLEDAD SAEZ; EDUARDO VALLI; ELENA RIVERA ; GABRIELA MARTIN

Breast Cancer-Carcinogenesis, Cell Growth and Signalling Pathways

Intech

Lugar: Rijeka; Año: 2011; p. 611 - 634

Metastases are the most devastating aspect of cancer since most deaths from cancer are related to them. The ability of tumors to invade the neighboring extracellular matrix is critical for the metastases, which is primarily accompanied by augmented matrix metalloproteinases (MMPs) production and cell migration. After surgical removal of primary breast tumors, malignant cells may still remain and radiotherapy is an efficient modality to reduce the risk of local recurrence. However, proliferative, invasive, and metastatic capacities can be increased in the surviving tumor cells of irradiated breast and many other neoplasias.To improve the efficacy of radiotherapy, this phenomenon must be further studied to elaborate therapeutic modalities to prevent radiation enhancement of cancer cell invasion.Histamine (HA) is a biogenic amine which exerts multiple functions in physiologic and pathophysiologic processes by stimulation of four G-protein coupled receptors (H1, H2, H3 and H4 histamine receptors). It is well known that several tumor tissues and cell lines express HA receptors through which HA exerts its effects on cell proliferation, differentiation, survival and death. A great deal of reports show a relevant role of HA in tumor progression, however controversial results are published depending on the cell type and the HA receptor subtype that is activated. Additionally some effects on tumor growth may be mediated by HA regulation of angiogenesis and immunity. HA and antihistamines have a modulatory effect on epithelial and endothelial cell adhesion and on the expression of different MMPs, however most of these reports refer to normal cells, existing less information regarding to tumor cells.Reactive oxygen species (ROS) such as superoxide anion and hydrogen peroxide (H2O2) are continuously produced as by-products of aerobic metabolism. In addition, external agents like ultraviolet radiation and ionizing radiation also increase intracellular ROS levels.  Though ROS may induce cellular damage when there is an imbalance among their generation and scavenging, numerous studies support the role of ROS as essential participants in cell signaling depending on their concentration, timing and location .The aim of the present study was to investigate the role of histamine and HA receptors activation in early cellular events involved in metastatic capacity. Since ionizing radiation may affect metastatic competence depending upon cell type and irradiation characteristics the possible interaction between histamine treatment and irradiation was also evaluated. Results showed that HA differentially regulates expression and activity of MMPs, cell migration and invasiveness through H2 and H4 receptors in MDA-MB 231 cells modulating H2O2 intracellular levels. Ionizing radiation increased ROS levels in irradiated control cells and a rise in MMPs activity and cell migration was also found . This effect observed on cellular events  elated to MDA-MB 231 invasiveness was counteracted when irradiated cells were treated with high doses of histamine or with H2 agonist, which may be due to the largest amount of ROS generated in these conditions. These results signal HA as a critical growth factor in MDA-MB 231 cells since it can modulate not only cell proliferation and death, as we have previously demonstrated, but also invasive capacity.