Targeting triple negative human breast cancer with omega-3 docosahexaenoic acid (DHA) and tocotrienol
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Triple negative breast cancers (TNBCs) account for ~15-20% of human breast cancers in Western countries. TNBCs are associated with poor prognosis and a low five year survival rate due, in part, to high rates of tumor recurrence, multi-drug resistance, metastasis, and therapeutic toxicity. Tumor initiating cells (TICs) or cancer stem cells (CSCs) are proposed to be responsible for the origin and maintenance of tumors as well as cancer recurrence, metastasis and drug resistance. Nutritionally-based low- to non-toxic therapeutic nutrients that eliminate both bulk tumor cells (non-TICs) and TICs have potential for prevention and treatment of primary and metastatic cancers, including TNBCs. Omega-3 fatty acid-docosahexaenoic acid (DHA) and certain vitamin E compounds [gamma- and delta- tocopherols [mathematical symbols] and tocotrienols [mathematical symbols]], separately and in combination, were investigated for their ability to eliminate non-TICs and TICs in human TNBCs and the mechanisms of action were studied. DHA induced apoptosis in several human TNBC cell lines via activation of endoplasmic-reticulum stress (ER stress) mediated C/EBP (CCAAT/enhancer binding protein) homologous protein (CHOP)/death receptor-5 (DR5) pro-apoptotic signaling involving caspases-8 and 9. DHA eliminated TICs as measured by elimination of aldehyde dehydrogenase active (ALDH⁺) population and inhibition of mammosphere formation. DHA eliminated TICs via suppression of phosphorylated Signal transducers and activators of transcription 3 (pStat-3) as well as downstream mediators cellular myelocytomatosis oncogene (c-Myc) and cyclin D1. SiRNA to Stat-3 reduced the number of ALDH⁺ TNBCs cells and reduced pStat-3, c-Myc, and cyclin D1 mediators, showing that Stat-3 is necessary for maintaining ALDH⁺ population and that c-Myc and cyclin D1 are downstream mediators of Stat-3. Studies also demonstrated that vitamin E compounds possess distinct anticancer activities. In summary, studies provide novel insights into therapeutic potential of DHA and certain vitamin E compounds for treatment of TNBCs.