Breast cancer cell growth can be inhibited in vivo by retinoid X receptor (RXR) specific retinoids. In both animal and cell culture studies, omega-3 fatty acids share growth regulatory effects similar to those of RXR specific retinoids (rexinoids). One synthetic rexinoid, bexarotene (LCD 1069, Targretin), is used clinically to treat cancer patients. Of concern is that some patients are unable to tolerate high doses of such treatment drugs. We hypothesized that n-3 fatty acids and bexarotene may work synergistically to slow breast cancer cell growth. To test our hypothesis, we used MCF-7 human mammary carcinoma cells and an in vitro cell culture model. We investigated the relationship between the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) alone and in conjunction with bexarotene in slowing MCF-7 cell growth. Following a 72 hr incubation with the respective treatments, bexarotene enhanced cell growth (p < 0.05) while DHA showed a strong growth inhibitory effect which was not enhanced by the addition of bexarotene (p < 0.05). EPA alone was not effective in altering cell growth (p < 0.05). Interestingly, when combined with bexarotene, EPA was more effective at slowing cell growth than when cells received EPA alone. Thus, select omega-3 fatty acids alone are more effective than bexarotene in slowing MCF-7 cell progression. However, the use of the RXR-selective retinoids may enhance the growth regulatory mechanisms of the fatty acid EPA.
A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu, T. Murray and M. J. Thun, “Cancer Statistics,” CA Cancer Journal for Clinicians, Vol. 58, No. 2, 2008, pp. 71-96. doi;10.3322/CA.2007.0010
N. F. Boyd, J. Stone, K. N. Vogt, B. S. Connelly, L. J. Martin and S. Minkin, “Dietary Fat and Breast Cancer Risk Revisited: A Meta-Analysis of the Published Literature,” British Journal of Cancer, Vol. 89, No. 9, 2003, pp. 1672-1685. doi;10.1038/sj.bjc.6601314
H. Rissanen, P. Knekt, R. Jarvinen, I. Salminen and T. Hakulinen, “Serum Fatty Acids and Breast Cancer Incidence,” Nutrition and Cancer, Vol. 45, No. 2, 2003, pp. 168-175. doi;10.1207/S15327914NC4502_05
E. Wirfalt, I. Mattisson, B. Gullberg, U. Johansson, H. Olsson and G. Berglund, “Postmenopausal Breast Cancer is Associated with High Intakes of ω6 Fatty Acids (Sweden),” Cancer Causes and Control, Vol. 13, No. 10, 2002, pp. 883-893. doi;10.1023/A:1021922917489
D. Bagga, K. H. Anders, H.-J. Wang and J. A. Glaspy, “Long-Chain n-3-to-n-6 Polyunsaturated Fatty Acid Ratios in Breast Adipose Tissue from Women with and without Breast Cancer,” Nutrition and Cancer, Vol. 42, No. 2, 2002, pp. 180-185. doi;10.1207/S15327914NC422_5
I. M. Berquin, I. J. Edwards and Y. Q. Chen, “Multi-Targeted Therapy of Cancer by Omega-3 Fatty Acids,” Cancer Letters, Vol. 269, No. 2, 2008, pp. 363-377. doi;10.1016/j.canlet.2008.03.044
C. M. Klass and D. M. Shin, “Current Status and Future Perspectives of Chemoprevention in Head and Neck Cancer,” Current Cancer Drug Targets, Vol. 7, No. 7, 2007, pp. 623-632. doi;10.2174/156800907782418347
M. Okuno, S. Kojima, R. Matsushima-Nishiwaki, H. Tsurumi, Y. Muto, S. L. Friedman and H. Moriwaki, “Retinoids in Cancer Chemoprevention,” Current Cancer Drug Targets, Vol. 4, No. 3, 2004, pp. 285-298. doi;10.2174/1568009043333023
J. Kim, S.-Y. Lim, A. Shin, M.-K. Sung, J. Ro, H.-S. Kang, K. Lee, S.-W. Kim and E.-S. Lee, “Fatty Fish and Fish Omega-3 Fatty Acid Intakes Decrease the Breast Cancer Risk: A Case-Control Study,” BMC Cancer, Vol. 9, 2009, p. 216. doi;10.1186/1471-2407-9-216
K. S. Kang, P. Wang, N. Yamabe, M. Fukui, T. Jay and B. T. Zhu, “Docosahexaenoic Acid Induces Apoptosis in MCF-7 Cells in Vitro and in Vivo Via Reactive Oxygen Species Formation and Caspase 8 Activation,” PLoS One, Vol. 5, No. 4, 2010, p. e10296.
P. Bougnoux, N. Hajjaji, M. N. Ferrasson, B. Giraudeau, C. Couet and O. Le Floch, “Improving Outcome of Chemotherapy of Metastatic Breast Cancer by Docosahexaenoic Acid: A Phase II trial,” British Journal of Cancer, Vol. 101, No. 12, 2009, pp. 1978-1985.
L. J. Hayden, S. N. Hawk, T. R. Sih and M. A. Satre, “Metabolic Conversion of Retinol to Retinoic Acid Mediates the Biological Responsiveness of Human Mammary Epithelial Cells to Retinol,” Journal of Cellular Physiology, Vol. 186, No. 3, 2001, pp. 437-447. doi;10.1002/1097-4652(2000)9999:999 3.0.CO;2-5
T. K. Hong and Y. C. Lee-Kim, “Effects of Retinoic Acid Isomers on Apoptosis and Enzymatic Antioxidant System in Human Breast Cancer Cells,” Nutrition Research Practice, Vol. 3, No. 2, 2009, pp. 77-83. doi;10.4162/nrp.2009.3.2.77
S. Toma, L. Isnardi, P. Raffo, G. Dastoli, E. DeFrancisci, L. Riccardi, R. Palumbo and W. Bollag, “Effects of All-Trans-Retinoic Acid and 13-Cis-Retinoic Acid on Breast Cancer Cell Lines: Growth Inhibition and Apoptosis Induction,” International Journal of Cancer, Vol. 70, No. 5, 1997, pp. 619-627. doi;10.1002/(SICI)1097-0215(19970304)70:5 3.0.CO;2-6
T. Camerini, L. Mariani, G. De Palo, E. Marubini, M. G. Di Mauro, A. Decensi, A. Costa and U. Veronesi, “Safety of the Synthetic Retinoid Fenretinide: Long-Term Results from a Controlled Clinical Trial for the Prevention of Contralateral Breast Cancer,” Journal of Clinical Oncology, Vol. 19, No. 6, 2001, pp. 1664-1670.
D. A. Brown, “The Effect of All-Trans Retinoic Acid and Fatty Acids on MCF-7 Breast Cancer Cell Progression,” MS Thesis, California Polytechnic State University, San Luis Obispo, 2009.
A. Dutta, T. Sen, A. Banerji, S. Das and A. Chatterjee, “Studies on Multifunctional Effect of All-Trans Retinoic Acid (ATRA) on Matrix Metalloproteinase-2 (MMP-2) and Its Regulatory Molecules in Human Breast Cancer Cells (MCF-7),” Journal of Oncology, Vol. 2009, 2009. http://www.hindawi.com/journals/jo/2009/627840/
G. J. Keiloff, C. W. Boone, J. A. Crowell, V. E. Steele, R. A. Lubet, L. A. Doody, W. F. Malone, E. T. Hawk and C. C. Sigman, “New Agents for Cancer Chemoprevention,” Journal of Cellular Biochemistry Supplement, Vol. 26, 1996, pp. 1-28.
F. Klamt, F. Dal-Pizzol, D. P. Gelain, R. S. Dalmolin, R. B. de Oliveira, M. Bastiani, F. Horn and J. C. F. Moreira, “Vitamin A Treatment Induces Apoptosis through an Oxidant-Dependent Activation of the Mitochondrial Pathway,” Cell Biology International, Vol. 32, No.1, 2008, pp. 100-106. doi;10.1016/j.cellbi.2007.08.018
R. Merino and J. M. Hurle, “The Molecular Basis of Retinoid Action in Tumors,” Trends in Molecular Medicine , Vol. 9, No. 12, 2003, pp. 509-511. doi;10.1016/j.molmed.2003.10.003
S. R. Thoennes, P. L. Tate, T. M. Price and M. W. Kilgore, “Differential Transcriptional Activation of Per- oxisome Proliferator-Activated Receptor Gamma by Omega-3 and Omega-6 Fatty Acids in MCF-7 Cells,” Molecular and Cellular Endocrinology, Vol. 160, No. 1-2, 2000, pp. 67-73. doi;10.1016/S0303-7207(99)00254-3
D. L. Crowe and R. A. Chandraratna, “A Retinoid X Receptor (RXR)-Selective Retinoid Reveals That RXR-Alpha Is Potentially a Therapeutic Target in Breast Cancer Cell Lines, and That It Potentiates Antiproliferative and Apoptotic Responses to Peroxisome Proliferator-Activated Receptor Ligands,” Breast Cancer Research, Vol. 6, No. 5, 2004, pp. R546-R555. doi;10.1186/bcr913
A. Chawla, J. J. Repa, R. M. Evans and D. J. Mangelsdorf, “Nuclear Receptors and Lipid Physiology: Opening the X-Files,” Science, Vol. 294, No. 5548, 2001, pp. 1866-1870. doi;10.1126/science.294.5548.1866
D. Bonofiglio, E. Cione, H. Qi, A. Pingitore, M. Perri, S. Catalano, D. Vizza, M. L. Panno, G. Genchi, S. A. Fuqua and S. Ando, “Combined Low Doses of PPARgamma and RXR Ligands Trigger an Intrinsic Apoptotic Pathway in Human Breast Cancer Cells,” American Journal of Pathology, Vol. 175, No. 3, 2009, pp. 1270-1280. doi;10.2353/ajpath.2009.081078
H.-S. Seo and J. S. Koo, “The Effect of Rexinoid (LGD 1069 and LG100268) on the Growth of Breast Cells,” Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Boston, 12-15 November 2006, p. A86.
W. C. Yen, R. Y. Prudente and W. W. Lamph, “Synergistic Effect of a Retinoid X Receptor-Selective Ligand Bexarotene (LGD1069, Targretin) and Paclitaxel (Taxol) in Mammary Carcinoma,” Breast Cancer Research and Treatment, Vol. 88, No. 2, 2004, pp. 141-148. doi;10.1007/s10549-004-1426-5
K. Novak, “Protein Kinase Inhibitors in Cancer Treatment: Mixing and Matching?” Keystone Symposium on Protein Kinases and Cancer, Vol. 6, No. 2, Lake Tahoe, California, February 2004.
L. A. de Graffenried, W. E. Friedrichs, L. Fulcher, G. Fernandes, J. M. Silva, J.-M. Peralba and M. Hidalgo, “Eicosapentaenoic Acid Restores Tamoxifen Sensitivity in Breast Cancer Cells with High Akt Activity,” Annals of Oncology, Vol. 14, No. 7, 2003, pp. 1051-1056. doi;10.1093/annonc/mdg291