The chemopreventive polyphenol Curcumin prevents hematogenous breast cancer metastases in immunodeficient mice

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 vitro and in a
mouse metastasis model. Curcumin strongly induces apoptosis in MDA-
MB- 231 cells in correlation with reduced activation of the
survival pathway NF kappa B, as a consequence of diminished I kappa
B and p65 phosphorylation. Curcumin also reduces the expression of
major matrix metalloproteinases (MMPs) due to reduced NF kappa B
activity and transcriptional downregulation of AP-1. NF kappa B/p65
silencing is sufficient to downregulate c-jun and MMP expression.
Reduced NF kappa 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 NF kappa 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. Copyright (c) 2007 S. Karger
AG, Basel.