title: The chemopreventive polyphenol Curcumin prevents hematogenous breast cancer metastases in immunodeficient mice.
abstract: Dissemination of metastatic cells probably occurs long before diagnosis of the primary tumor. Metastasis during early phases of carcinogenesis in high risk patients is therefore a potential prevention target. The plant polyphenol Curcumin has been proposed for dietary prevention of cancer. We therefore examined its effects on the human breast cancer cell line MDA-MB-231 in vitroand in a mouse metastasis model. Curcumin strongly induces apoptosis in MDA-MB-231 cells in correlation with reduced activation of the survival pathway NFkappaB, as a consequence of diminished IotakappaB and p65 phosphorylation. Curcumin also reduces the expression of major matrix metalloproteinases (MMPs) due to reduced NFkappa B activity and transcriptional downregulation of AP-1. NFkappa B/p65 silencing is sufficient to downregulate c-jun and MMP expression. Reduced NFkappa B/AP-1 activity and MMP expression lead to diminished invasion through a reconstituted basement membrane and to a significantly lower number of lung metastases in immunodeficient mice after intercardiac injection of 231 cells (p=0.0035). 68% of Curcumin treated but only 17% of untreated animals showed no or very few lung metastases, most likely as a consequence of down-regulation of NFkappa B/AP-1 dependent MMP expression and direct apoptotic effects on circulating tumor cells but not on established metastases. Dietary chemoprevention of metastases appears therefore feasible.
authors.affiliation: Department of Clinical Chemistry and Clinical Biochemistry, Surgical Hospital, Ludwig-Maximilians-University Munich, Germany. bachmeier@med.uni-muenchen.de
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bachmeier
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Nerlich
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Iancu
authors.forename: Michele
authors.initials: M
authors.lastname: Cilli
authors.forename: Erwin
authors.initials: E
authors.lastname: Schleicher
authors.forename: Roberta
authors.initials: R
authors.lastname: Vené
authors.forename: Raffaella
authors.initials: R
authors.lastname: Dell'Eva
authors.forename: Marianne
authors.initials: M
authors.lastname: Jochum
authors.forename: Adriana
authors.initials: A
authors.lastname: Albini
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pfeffer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003474:Curcumin / Q000494:pharmacology*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000235:genetics; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D010636:Phenols / Q000494:pharmacology*; D010766:Phosphorylation; D059808:Polyphenols; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D051858:Forkhead Transcription Factors; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; D010636:Phenols; D059808:Polyphenols; D018808:Transcription Factor AP-1; C090140:Whn protein; D020782:Matrix Metalloproteinases; D003474:Curcumin