The data derived from epidemiological and animal models confirm a beneficial effect of fish oil (rich in omega-3 polyunsaturated fatty acids) in the amelioration of tumor growth and progression including breast cancer The breast cancer patients often develop bone metastasis evidenced by osteolytic lesions leading to severe pain and bone fracture Using a mouse model of MDA-MB-231 human breast cancer cell metastasis to bone here we show that fish oil diet enriched in DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) prevents the formation of osteolytic lesions in bone indicating suppression of cancer cell metastasis to bone These results are supported by our data showing both DHA and EPA significantly attenuate the migration/invasion of MDA-MB-231 breast cancer cells in culture The mechanism that limits breast cancer cells to selective metastasis to bone remains hitherto unexplored Aberrant Increased expression of CD44 is associated with generation of cancer stem cells which contribute to metastasis of breast cancer cells We demonstrate that DHA and EPA significantly inhibit the expression of CD44 protein and mRNA by a transcriptional mechanism Furthermore we show markedly reduced levels of CD44 mRNA and protein in the tumors of mice which were fed fish oil diet than those in control diet Our data provide the first evidence for a salutary effect of fish oil on breast cancer metastasis to bone Our results identify a novel function of the fish oil active components DHA and EPA which target the cell-intrinsic pro-metastatic molecule CD44 to inhibit migration/invasion Published by Elsevier Inc