Histamine Inhibits Proliferation through the Four Histamine Receptor Subtypes in MCF-7 Human Breast Cancer Cell Line

MEDINA VANINA; MASSARI NOELIA; NUñEZ MARIEL; CRICCO GRACIELA; MARTIN GABRIELA; BERGOC ROSA; RIVERA ELENA

Estocolmo, Suecia

Congreso; European Histamine Research Society, XXVII Annual Meeting; 2008

European Histamine Research Society

We have reported that histamine (HA) regulates differentially signaling processes in HBL-100 normal and MDA-MB-231 malignant [estrogen receptor (ER) á-] human breast cells. The aim of the present study was to investigate the biological responses triggered by HA in MCF-7 (ERá+) breast cancer cells. For this purpose we determined the expression of the HA receptors (HR) subtypes, H1R, H2R, H3R and H4R by RT-PCR; histidine decarboxylase (HDC) by western blot; HA content by immunostaining; cAMP production by RIA; cell proliferation by the clonogenic assay; differentiation by Nile red staining and flow cytometry; and apoptosis by flow cytometry and TUNEL assay. Results indicate that MCF-7 cells expressed the four HA receptors, HDC and presented a moderate level of intracellular HA. HA treatment (10 µM) produced a 2-fold increase in cAMP levels and reduced cell proliferation (30%). Lower HA doses also decreased proliferation. By using specific HA agonist and antagonist, we determined that HA decreased proliferation through the stimulation of the four HA receptors subtypes however, the most significant effect was exerted via H4R (70%). HA was unable to promote differentiation in these cells. On the other hand, the inhibitory effect of HA on proliferation was associated with an induction of apoptosis after 72 h of treatment. Present results show that HA was incapable of inducing proliferation via the H3R in these cells as compared with the more undifferentiated MDA-MB-231 breast cancer suggesting that different isoform expression, protein-protein interactions, or localization could be responsible for the differences in the signaling pathways.