DHA is a more potent inhibitor of breast cancer metastasis to bone and related osteolysis than EPA
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Breast cancer patients often develop bone metastasis evidenced by osteolytic lesions, leading to severe pain and bone fracture. Attenuation of breast cancer metastasis to bone and associated osteolysis by fish oil, rich in EPA and DHA, has been demonstrated previously. However, it was not known whether EPA and DHA differentially or similarly affect breast cancer bone metastasis and associated osteolysis. In vitro culture of parental and luciferase gene encoded MDA-MB-231 human breast cancer cell lines treated with EPA and DHA revealed that DHA inhibits proliferation and invasion of breast cancer cells more potently than EPA. Intra-cardiac injection of parental and luciferase gene encoded MDA-MB-231 cells to athymic NCr nu/nu mice demonstrated that DHA-treated mice had significantly less breast cancer cell burden in bone, and also significantly less osteolytic lesions than EPA-treated mice. In vivo cell migration assay as measured by luciferase intensity revealed that DHA attenuated cell migration specifically to the bone. Moreover, the DHA-treated group showed reduced levels of CD44 and TRAP positive area in bone compared to EPA-treated group. Breast cancer cell burden and osteolytic lesions were also examined in intra-tibially breast cancer cell injected mice and found less breast cancer cell growth and associated osteolysis in DHA-treated mice as compared to EPA-treated mice. Finally, doxorubicin-resistant MCF-7 (MCF-7dox) human breast cancer cell line was used to examine if DHA can improve sensitization of MCF-7dox cells to doxorubicin. DHA improved the inhibitory effect of doxorubicin on proliferation and invasion of MCF-7dox cells. Interestingly, drug resistance gene P-gp was also down-regulated in DHA plus doxorubicin-treated cells. In conclusion, DHA attenuates breast cancer bone metastasis and associated osteolysis more potently than EPA, possibly by inhibiting migration of breast cancer cell to the bone as well as by inhibiting osteoclastic bone resorption.
KeywordsBreast cancer Bone metastasis Omega-3 fatty acids Docosahexaenoic acid Osteolysis
We acknowledge Emily Molina for her kind review of our manuscript for grammatical corrections. We thank Ocean Nutrition Canada for free supply of FO-EPA and FO-DHA for this study. This study was supported by DOD, BC096459, Elsa U. Pardee Foundation 131884/44096 and NIH AG034233 grants.
Conflict of interest
The authors declare that they have no conflict of interest.
- 8.Rovito D, Giordano C, Vizza D, Plastina P, Barone I, Casaburi I, Lanzino M, De Amicis F, Sisci D, Mauro L, Aquila S, Catalano S, Bonofiglio D, Ando S (2013) Omega-3 PUFA ethanolamides DHEA and EPEA induce autophagy through PPARgamma activation in MCF-7 breast cancer cells. J Cell Physiol 228:1314–1322PubMedCrossRefGoogle Scholar
- 27.Nawata K, Yamauchi M, Takaoka S, Yamaguchi T, Sugimoto T (2013) Association of n-3 polyunsaturated fatty acid intake with bone mineral density in postmenopausal women. Calcif Tissue Int 93(2):147–54Google Scholar
- 28.Farina EK, Kiel DP, Roubenoff R, Schaefer EJ, Cupples LA, Tucker KL (2011) Protective effects of fish intake and interactive effects of long-chain polyunsaturated fatty acid intakes on hip bone mineral density in older adults: the Framingham Osteoporosis Study. Am J Clin Nutr 93:1142–1151PubMedCrossRefGoogle Scholar
- 29.Lage S, Bueno M, Andrade F, Prieto JA, Delgado C, Legarda M, Sanjurjo P, Aldamiz-Echevarria LJ (2010) Fatty acid profile in patients with phenylketonuria and its relationship with bone mineral density. J Inherit Metab Dis 33 Suppl 3:363–71Google Scholar
- 32.Oliver E, McGillicuddy FC, Harford KA, Reynolds CM, Phillips CM, Ferguson JF, Roche HM (2012) Docosahexaenoic acid attenuates macrophage-induced inflammation and improves insulin sensitivity in adipocytes-specific differential effects between LC n-3 PUFA. J Nutr Biochem 23:1192–1200PubMedCrossRefGoogle Scholar
- 34.Martinez-Micaelo N, Gonzalez-Abuin N, Terra X, Richart C, Ardevol A, Pinent M, Blay M (2012) Omega-3 docosahexaenoic acid and procyanidins inhibit cyclo-oxygenase activity and attenuate NF-kappaB activation through a p105/p50 regulatory mechanism in macrophage inflammation. Biochem J 441:653–663PubMedCrossRefGoogle Scholar
- 43.Serini S, Trombino S, Oliva F, Piccioni E, Monego G, Resci F, Boninsegna A, Picci N, Ranelletti FO, Calviello G (2008) Docosahexaenoic acid induces apoptosis in lung cancer cells by increasing MKP-1 and down-regulating p-ERK1/2 and p-p38 expression. Apoptosis 13:1172–1183PubMedCrossRefGoogle Scholar
- 60.Menendez JA, Lupu R, Colomer R (2005) Exogenous supplementation with omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA; 22:6n-3) synergistically enhances taxane cytotoxicity and downregulates Her-2/neu (c-erbB-2) oncogene expression in human breast cancer cells. Eur J Cancer Prev 14:263–270PubMedCrossRefGoogle Scholar