title: Characterization of synergistic anti-cancer effects of docosahexaenoic acid and curcumin on DMBA-induced mammary tumorigenesis in mice.
abstract: BACKGROUND
  The major obstacles to the successful use of individual nutritional compounds as preventive or therapeutic agents are their efficacy and bioavailability. One approach to overcoming this problem is to use combinations of nutrients to induce synergistic effects. The objective of this research was to investigate the synergistic effects of two dietary components: docosahexaenoic acid (DHA), an omega-3 fatty acid present in cold-water fish, and curcumin (CCM), an herbal nutrient present in turmeric, in an in vivo model of DMBA-induced mammary tumorigenesis in mice.
  
  
  METHODS
  We used the carcinogen DMBA to induce breast tumors in SENCAR mice on control, CCM, DHA, or DHA + CCM diets. Appearance and tumor progression were monitored daily. The tumors were harvested 15 days following their first appearance for morphological and immunohistological analysis. Western analysis was performed to determine expression of maspin and survivin in the tumor tissues. Characterization of tumor growth was analyzed using appropriate statistical methods. Otherwise all other results are reported as mean ± SD and analyzed with one-way ANOVA and Tukey's post hoc procedure.
  
  
  RESULTS
  Analysis of gene microarray data indicates that combined treatment with DHA + CCM altered the profile of "PAM50" genes in the SK-BR-3 cell line from an ER⁻/Her-2⁺ to that resembling a "normal-like" phenotype. The in vivo studies demonstrated that DHA + CCM treatment reduced the incidence of breast tumors, delayed tumor initiation, and reduced progression of tumor growth. Dietary treatment had no effect on breast size development, but tumors from mice on a control diet (untreated) were less differentiated than tumors from mice fed CCM or DHA + CCM diets. The synergistic effects also led to increased expression of the pro-apoptotic protein, maspin, but reduced expression of the anti-apoptotic protein, survivin.
  
  
  CONCLUSIONS
  The SK-BR-3 cells and DMBA-induced tumors, both with an ER⁻ and Her-2⁺ phenotype, were affected by the synergistic interaction of DHA and CCM. This suggests that the specific breast cancer phenotype is an important factor for predicting efficacy of these nutraceuticals. The combination of DHA and CCM is potentially a dietary supplemental treatment for some breast cancers, likely dependent upon the molecular phenotype of the cancer.
authors.affiliation: Cellular Biochemistry Laboratory, Indiana University Health, Indianapolis, IN 46202, USA. rsiddiqu@iuhealth.org.
authors.forename: Rafat A
authors.initials: RA
authors.lastname: Siddiqui
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Harvey
authors.forename: Candace
authors.initials: C
authors.lastname: Walker
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Altenburg
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Xu
authors.forename: Colin
authors.initials: C
authors.lastname: Terry
authors.forename: Ignacio
authors.initials: I
authors.lastname: Camarillo
authors.forename: Yava
authors.initials: Y
authors.lastname: Jones-Hall
authors.forename: Cary
authors.initials: C
authors.lastname: Mariash
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000009:adverse effects; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D016000:Cluster Analysis; D003474:Curcumin / Q000008:administration & dosage / Q000494:pharmacology*; D004032:Diet; D004281:Docosahexaenoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015843:Serpins / Q000235:genetics / Q000378:metabolism; D000077022:Survivin; D047368:Tumor Burden; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics
chemical_list: D015127:9,10-Dimethyl-1,2-benzanthracene; D000970:Antineoplastic Agents; D003474:Curcumin; D004281:Docosahexaenoic Acids; D051034:Inhibitor of Apoptosis Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D015843:Serpins; D000077022:Survivin; C107489:BIRC5 protein, human; C085344:SERPIN-B5
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