title: Histamine prevents radiation-induced mesenchymal changes in breast cancer cells.
abstract: Radiotherapy is a prime option for treatment of solid tumors including breast cancer though side effects are usually present. Experimental evidence shows an increase in invasiveness of several neoplastic cell types through conventional tumor irradiation. The induction of epithelial to mesenchymal transition is proposed as an underlying cause of metastasis triggered by gamma irradiation. Experiments were conducted to investigate the role of histamine on the ionizing radiation-induced epithelial to mesenchymal transition events in breast cancer cells with different invasive phenotype. We also evaluated the potential involvement of Src phosphorylation in the migratory capability of irradiated cells upon histamine treatment. MCF-7 and MDA-MB-231 mammary tumor cells were exposed to a single dose of 2Gy of gamma radiation and five days after irradiation mesenchymal-like phenotypic changes were observed by optical microscope. The expression and subcellular localization of E-cadherin, β-catenin, vimentin and Slug were determined by immunoblot and indirect immunofluorescence. There was a decrease in the epithelial marker E-cadherin expression and an increase in the mesenchymal marker vimentin after irradiation. E-cadherin and β-catenin were mainly localized in cytoplasm. Slug positive nuclei, matrix metalloproteinase-2 activity and cell migration and invasion were significantly increased. In addition, a significant enhancement in Src phosphorylation/activation could be determined by immunoblot in irradiated cells. MCF-7 and MDA-MB-231 cells also received 1 or 20μM histamine during 24h previous to be irradiated. Notably, pre-treatment of breast cancer cells with 20μM histamine prevented the mesenchymal changes induced by ionizing radiation and also reduced the migratory behavior of irradiated cells decreasing phospho-Src levels. Collectively, our results suggest that histamine may block events related to epithelial to mesenchymal transition in irradiated mammary cancer cells and open a perspective for the potential use of histamine to improve radiotherapy efficacy.
authors.affiliation: Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Laboratorio de Radioisótopos, Buenos Aires, Argentina.
authors.forename: Tamara E
authors.initials: TE
authors.lastname: Galarza
authors.affiliation: Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Laboratorio de Radioisótopos, Buenos Aires, Argentina.
authors.forename: Nora A
authors.initials: NA
authors.lastname: Mohamad
authors.affiliation: Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Laboratorio de Radioisótopos, Buenos Aires, Argentina.
authors.forename: Mónica A
authors.initials: MA
authors.lastname: Táquez Delgado
authors.affiliation: Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Laboratorio de Radioisótopos, Buenos Aires, Argentina.
authors.forename: Guadalupe M
authors.initials: GM
authors.lastname: Vedoya
authors.affiliation: Instituto de Inmunooncología, Buenos Aires, Argentina.
authors.forename: Ernesto J
authors.initials: EJ
authors.lastname: Crescenti
authors.affiliation: Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Bergoc
authors.affiliation: Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Laboratorio de Radioisótopos, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
authors.forename: Gabriela A
authors.initials: GA
authors.lastname: Martín
authors.affiliation: Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Laboratorio de Radioisótopos, Buenos Aires, Argentina. Electronic address: gracrico@ffyb.uba.ar.
authors.forename: Graciela P
authors.initials: GP
authors.lastname: Cricco
mesh_terms: D015703:Antigens, CD; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects* / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000528:radiation effects; D005260:Female; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness; D010641:Phenotype; D010766:Phosphorylation; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D011878:Radiotherapy / Q000009:adverse effects; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D011837:Radiation-Protective Agents; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014746:Vimentin; D051176:beta Catenin; D006632:Histamine; D019061:src-Family Kinases
keywords: Breast cancer; Epithelial to mesenchymal transition; Histamine; Histamine (PubChem CID: 774); Ionizing radiation; PP2 (PubChem CID: 4878); Src