Increasing evidence shows the beneficial effects of fish oil on breast cancer 
growth and invasion in vitro and in animal models. Expression of CSF-1 (colony 
stimulating factor-1) by breast cancer cells acts as potent activator of 
malignancy and metastasis. In this report, we used two human breast cancer cell 
lines, MDA-MB-231 and MCF-7, to show that the bioactive fish oil component DHA 
(docosahexaenoic acid) inhibits expression of CSF-1 and its secretion from these 
cancer cells. We found that the tumor suppressor protein PTEN regulates CSF-1 
expression through PI 3 kinase/Akt signaling via a transcriptional mechanism. 
The enhanced abundance of microRNA-21 (miR-21) in breast cancer cells 
contributes to the growth and metastasis. Interestingly, DHA significantly 
inhibited expression of miR-21. miR-21 Sponge, which derepresses the miR-21 
targets, markedly decreased expression of CSF-1 and its secretion. Furthermore, 
miR-21-induced upregulation of CSF-1 mRNA and its transcription were prevented 
by expression of PTEN mRNA lacking 3'-untranslated region (UTR) and miR-21 
recognition sequence. Strikingly, miR-21 reversed DHA-forced reduction of CSF-1 
expression and secretion. Finally, we found that expression of miR-21 as well as 
CSF-1 was significantly attenuated in breast tumors of mice receiving a diet 
supplemented with fish oil. Our results reveal a novel mechanism for the 
therapeutic function of fish oil diet that blocks miR-21, thereby increasing 
PTEN levels to prevent expression of CSF-1 in breast cancer.