Top

Published in:

Open Access 01-12-2016 | Research

Role of a polyphenol-enriched preparation on chemoprevention of mammary carcinoma through cancer stem cells and inflammatory pathways modulation

Authors: Tri Vuong, Jean-François Mallet, Maria Ouzounova, Sam Rahbar, Hector Hernandez-Vargas, Zdenko Herceg, Chantal Matar

Published in: Journal of Translational Medicine | Issue 1/2016

Abstract

Background

Naturally occurring polyphenolic compounds from fruits, particularly from blueberries, have been reported to be significantly involved in cancer chemoprevention and chemotherapy. Biotransformation of blueberry juice by Serratia vaccinii increases its polyphenolic content and endows it with anti-inflammatory properties.

Methods

This study evaluated the effect of a polyphenol-enriched blueberry preparation (PEBP) and its non-fermented counterpart (NBJ), on mammary cancer stem cell (CSC) development in in vitro, in vivo and ex vivo settings. Effects of PEBP on cell proliferation, mobility, invasion, and mammosphere formation were measured in vitro in three cell lines: murine 4T1 and human MCF7 and MDA-MB-231. Ex vivo mammosphere formation, tumor growth and metastasis observations were carried out in a BALB/c mouse model.

Results

Our research revealed that PEBP influence cellular signaling cascades of breast CSCs, regulating the activity of transcription factors and, consequently, inhibiting tumor growth in vivo by decreasing metastasis and controlling PI3K/AKT, MAPK/ERK, and STAT3 pathways, central nodes in CSC inflammatory signaling. PEBP significantly inhibited cell proliferation of 4T1, MCF-7 and MDA-MB-231. In all cell lines, PEBP reduced mammosphere formation, cell mobility and cell migration. In vivo, PEBP significantly reduced tumor development, inhibited the formation of ex vivo mammospheres, and significantly reduced lung metastasis.

Conclusions

This study showed that polyphenol enrichment of a blueberry preparation by fermentation increases its chemopreventive potential by protecting mice against tumor development, inhibiting the formation of cancer stem cells and reducing lung metastasis. Thus, PEBP may represent a novel complementary alternative medicine therapy and a source for novel therapeutic agents against breast cancer.

Slattery ML, Lundgreen A, Torres-Mejia G, Wolff RK, Hines L, Baumgartner K, et al. Diet and lifestyle factors modify immune/inflammation response genes to alter breast cancer risk and prognosis: the Breast Cancer Health Disparities Study. Mutat Res. 2014;770:19–28.PubMedPubMedCentralCrossRef

Villarini A, Pasanisi P, Traina A, Mano MP, Bonanni B, Panico S, et al. Lifestyle and breast cancer recurrences: the DIANA-5 trial. Tumori. 2012;98:1–18.PubMed

Greenlee H, Balneaves LG, Carlson LE, Cohen M, Deng G, Hershman D, et al. Clinical practice guidelines on the use of integrative therapies as supportive care in patients treated for breast cancer. JNCI Monogr. 2014;2014:346–58.CrossRef

Rossi T, Gallo C, Bassani B, Canali S, Albini A, Bruno A. Drink your prevention: beverages with cancer preventive phytochemicals. Pol Arch Med Wewnętrznej. 2014;124:713–22.

Kanaya N, Adams L, Takasaki A, Chen S. Whole blueberry powder inhibits metastasis of triple negative breast cancer in a xenograft mouse model through modulation of inflammatory cytokines. Nutr Cancer. 2014;66:242–8.PubMedCrossRef

Montales MTE, Rahal OM, Kang J, Rogers TJ, Prior RL, Wu X, et al. Repression of mammosphere formation of human breast cancer cells by soy isoflavone genistein and blueberry polyphenolic acids suggests diet-mediated targeting of cancer stem-like/progenitor cells. Carcinogenesis. 2012;33:652–60.PubMedCrossRef

Nguyen V, Tang J, Oroudjev E, Lee CJ, Marasigan C, Wilson L, et al. Cytotoxic effects of bilberry extract on MCF7-GFP-tubulin breast cancer cells. J Med Food. 2010;13:278–85.PubMedCrossRef

Martin LJ, Matar C. Increase of antioxidant capacity of the lowbush blueberry (Vaccinium angustifolium) during fermentation by a novel bacterium from the fruit microflora. J Sci Food Agric. 2005;85:1477–84.CrossRef

Graziano A, d’Aquino R, Tirino V, Desiderio V, Rossi A, Pirozzi G. The stem cell hypothesis in head and neck cancer. J Cell Biochem. 2008;103:408–12.PubMedCrossRef

10.

O’Connor ML, Xiang D, Shigdar S, Macdonald J, Li Y, Wang T, et al. Cancer stem cells: a contentious hypothesis now moving forward. Cancer Lett. 2014;344:180–7.PubMedCrossRef

11.

Camerlingo R, Ferraro GA, De Francesco F, Romano M, Nicoletti G, Di Bonito M, et al. The role of CD44+/CD24−/low biomarker for screening, diagnosis and monitoring of breast cancer. Oncol Rep. 2014;31:1127–32.PubMed

12.

Podberezin M, Wen J, Chang CC. Cancer stem cells: a review of potential clinical applications. Arch Pathol Lab Med. 2013;137:1111–6.PubMedCrossRef

13.

Chang Q, Bournazou E, Sansone P, Berishaj M, Gao SP, Daly L, et al. The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis. Neoplasia. 2013;15:848–62.PubMedPubMedCentralCrossRef

14.

Lamy S, Akla N, Ouanouki A, Lord-Dufour S, Beliveau R. Diet-derived polyphenols inhibit angiogenesis by modulating the interleukin-6/STAT3 pathway. Exp Cell Res. 2012;318:1586–96.PubMedCrossRef

15.

Zhao X, Sun X, Li X. Expression and clinical significance of STAT3, P-STAT3, and VEGF-C in small cell lung cancer. Asian Pac J Cancer Prev APJCP. 2012;13:2873–7.PubMedCrossRef

16.

Hernandez-Vargas H, Ouzounova M, Le Calvez-Kelm F, Lambert M-P, McKay-Chopin S, Tavtigian SV, et al. Methylome analysis reveals Jak-STAT pathway deregulation in putative breast cancer stem cells. Epigenetics. 2011;6:428–39.PubMedCrossRef

17.

Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.PubMedCrossRef

18.

Yip NC, Fombon IS, Liu P, Brown S, Kannappan V, Armesilla AL, et al. Disulfiram modulated ROS-MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties. Br J Cancer. 2011;104:1564–74.PubMedPubMedCentralCrossRef

19.

Chen J, Sun WL, Wasylyk B, Wang YP, Zheng H. c-Jun N-terminal kinase mediates microtubule-depolymerizing agent-induced microtubule depolymerization and G2/M arrest in MCF-7 breast cancer cells. Anticancer Drugs. 2012;23:98–107.PubMedCrossRef

20.

Wagner EF, Nebreda AR. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 2009;9:537–49.PubMedCrossRef

21.

Balko JM, Schwarz LJ, Bhola NE, Kurupi R, Owens P, Miller TW, et al. Activation of MAPK pathways due to DUSP4 loss promotes cancer stem cell-like phenotypes in basal-like breast cancer. Cancer Res. 2013;73:6346–58.PubMedPubMedCentralCrossRef

22.

Vuong T, Martin L, Matar C. Antioxidant activity of fermented berry juices and their effects on nitric oxide and tumor necrosis factor-alpha production in macrophages 264.7 gamma no(–) Cell line. J Food Biochem. 2006;30:249–68.CrossRef

23.

Vuong T, Matar C, Ramassamy C, Haddad PS. Biotransformed blueberry juice protects neurons from hydrogen peroxide-induced oxidative stress and mitogen-activated protein kinase pathway alterations. Br J Nutr. 2010;104:656–63.PubMedCrossRef

24.

Vuong T, Benhaddou-Andaloussi A, Brault A, Harbilas D, Martineau LC, Vallerand D, et al. Antiobesity and antidiabetic effects of biotransformed blueberry juice in KKAy mice. Int J Obes. 2009;33:1166–73.CrossRef

25.

Vuong T, Martineau LC, Ramassamy C, Matar C, Haddad PS. Fermented Canadian lowbush blueberry juice stimulates glucose uptake and AMP-activated protein kinase in insulin-sensitive cultured muscle cells and adipocytes. Can J Physiol Pharmacol. 2007;85:956–65.PubMedCrossRef

26.

Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004;114:1752–61.PubMedPubMedCentralCrossRef

27.

Bruun JM, Lihn AS, Verdich C, Pedersen SB, Toubro S, Astrup A, et al. Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans. Am J Physiol Endocrinol Metab. 2003;285:E527–33.PubMedCrossRef

28.

Lashinger LM, Ford NA, Hursting SD. Interacting inflammatory and growth factor signals underlie the obesity-cancer link. J Nutr. 2014;144:109–13.PubMedPubMedCentralCrossRef

29.

Matchett MD, MacKinnon SL, Sweeney MI, Gottschall-Pass KT, Hurta RA. Inhibition of matrix metalloproteinase activity in DU145 human prostate cancer cells by flavonoids from lowbush blueberry (Vaccinium angustifolium): possible roles for protein kinase C and mitogen-activated protein-kinase-mediated events. J Nutr Biochem. 2006;17:117–25.PubMedCrossRef

30.

Zhou Y, Su J, Shi L, Liao Q, Su Q. DADS downregulates the Rac1-ROCK1/PAK1-LIMK1-ADF/cofilin signaling pathway, inhibiting cell migration and invasion. Oncol Rep. 2013;29:605–12.PubMed

31.

Partridge J, Flaherty P. An in vitro FluoroBlok tumor invasion assay. J Vis Exp. 2009; 29.

32.

Pulaski BA, Ostrand-Rosenberg S. Mouse 4T1 breast tumor model. Curr Protoc Immunol. 2001; Chapter 20: Unit 20.2.

33.

Yang CS, Sang S, Lambert JD, Lee M-J. Bioavailability issues in studying the health effects of plant polyphenolic compounds. Mol Nutr Food Res. 2008;52(Suppl 1):S139–51.PubMed

34.

Davis BJ, Xie Z, Viollet B, Zou M-H. Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes. 2006;55:496–505.PubMedCrossRef

35.

Guigas B, Bertrand L, Taleux N, Foretz M, Wiernsperger N, Vertommen D, et al. 5-Aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside and metformin inhibit hepatic glucose phosphorylation by an AMP-activated protein kinase-independent effect on glucokinase translocation. Diabetes. 2006;55:865–74.PubMedCrossRef

36.

Jung J-W, Park S-B, Lee S-J, Seo M-S, Trosko JE, Kang K-S. Metformin represses self-renewal of the human breast carcinoma stem cells via inhibition of estrogen receptor-mediated OCT4 expression. PLoS One. 2011;6:e28068.PubMedPubMedCentralCrossRef

37.

Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 2009;69:7507–11.PubMedPubMedCentralCrossRef

38.

Adams LS, Phung S, Yee N, Seeram NP, Li L, Chen S. Blueberry phytochemicals inhibit growth and metastatic potential of MDA-MB-231 breast cancer cells through modulation of the phosphatidylinositol 3-kinase pathway. Cancer Res. 2010;70:3594–605.PubMedPubMedCentralCrossRef

39.

Faria A, Pestana D, Teixeira D, de Freitas V, Mateus N, Calhau C. Blueberry anthocyanins and pyruvic acid adducts: anticancer properties in breast cancer cell lines. Phytother Res. 2012;24:1862–9.CrossRef

40.

Fraga CG, Galleano M, Verstraeten SV, Oteiza PI. Basic biochemical mechanisms behind the health benefits of polyphenols. Mol Aspects Med. 2010;31:435–45.PubMedCrossRef

41.

Subbaramaiah K, Sue E, Bhardwaj P, Du B, Hudis CA, Giri D, et al. Dietary polyphenols suppress elevated levels of proinflammatory mediators and aromatase in the mammary gland of obese mice. Cancer Prev Res. 2013;6:886–97.CrossRef

42.

Iliopoulos D, Hirsch HA, Wang G, Struhl K. Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci USA. 2011;108:1397–402.PubMedPubMedCentralCrossRef

43.

Iliopoulos D, Hirsch HA, Struhl K. An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell. 2009;139:693–706.PubMedPubMedCentralCrossRef

44.

Koul HK, Pal M, Koul S. Role of p38 MAP kinase signal transduction in solid tumors. Genes Cancer. 2013;4:342–59.PubMedPubMedCentralCrossRef

45.

Hirsch HA, Iliopoulos D, Struhl K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci USA. 2013;110:972–7.PubMedPubMedCentralCrossRef

46.

Mauer J, Denson JL, Brüning JC. Versatile functions for IL-6 in metabolism and cancer. Trends Immunol. 2015;36:92–101.PubMedCrossRef

47.

Cheng JQ, Godwin AK, Bellacosa A, Taguchi T, Franke TF, Hamilton TC, et al. AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc Natl Acad Sci USA. 1992;89:9267–71.PubMedPubMedCentralCrossRef

48.

Bellacosa A, de Feo D, Godwin AK, Bell DW, Cheng JQ, Altomare DA, et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer J Int Cancer. 1995;64:280–5.CrossRef

49.

Korkaya H, Liu S, Wicha MS. Regulation of cancer stem cells by cytokine networks: attacking cancer’s inflammatory roots. Clin Cancer Res Off J Am Assoc Cancer Res. 2011;17:6125–9.CrossRef

50.

Bowers LW, Cavazos DA, Maximo IXF, Brenner AJ, Hursting SD, deGraffenried LA. Obesity enhances nongenomic estrogen receptor crosstalk with the PI3K/Akt and MAPK pathways to promote in vitro measures of breast cancer progression. Breast Cancer Res. 2013;15:R59.PubMedPubMedCentralCrossRef

51.

Liu Z-L, Wang H, Liu J, Wang Z-X. MicroRNA-21 (miR-21) expression promotes growth, metastasis, and chemo- or radioresistance in non-small cell lung cancer cells by targeting PTEN. Mol Cell Biochem. 2013;372:35–45.PubMedCrossRef

52.

Chen J, Sun L. Formononetin-induced apoptosis by activation of Ras/p38 mitogen-activated protein kinase in estrogen receptor-positive human breast cancer cells. Horm Metab Res Horm Stoffwechselforschung Horm Métabolisme. 2012;44:943–8.CrossRef

53.

Na H-K, Kim E-H, Choi M-A, Park J-M, Kim D-H, Surh Y-J. Diallyl trisulfide induces apoptosis in human breast cancer cells through ROS-mediated activation of JNK and AP-1. Biochem Pharmacol. 2012;84:1241–50.PubMedCrossRef

54.

Leisner TM, Moran C, Holly SP, Parise LV. CIB1 prevents nuclear GAPDH accumulation and non-apoptotic tumor cell death via AKT and ERK signaling. Oncogene. 2013;32:4017–27.PubMedPubMedCentralCrossRef

55.

Yang L-H, Ho Y-J, Lin J-F, Yeh C-W, Kao S-H, Hsu L-S. Butein inhibits the proliferation of breast cancer cells through generation of reactive oxygen species and modulation of ERK and p38 activities. Mol Med Rep. 2012;6:1126–32.PubMed

56.

Pulaski BA, Ostrand-Rosenberg S. Reduction of established spontaneous mammary carcinoma metastases following immunotherapy with major histocompatibility complex class II and B7.1 cell-based tumor vaccines. Cancer Res. 1998;58:1486–93.PubMed

57.

Lelekakis M, Moseley JM, Martin TJ, Hards D, Williams E, Ho P, et al. A novel orthotopic model of breast cancer metastasis to bone. Clin Exp Metastasis. 1999;17:163–70.PubMedCrossRef

58.

Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008;22:659–61.PubMedCrossRef

59.

Mykkänen OT, Huotari A, Herzig K-H, Dunlop TW, Mykkänen H, Kirjavainen PV. Wild blueberries (Vaccinium myrtillus) alleviate inflammation and hypertension associated with developing obesity in mice fed with a high-fat diet. PLoS One. 2014;9:e114790.PubMedPubMedCentralCrossRef

60.

Perez-Jimenez J, Fezeu L, Touvier M, Arnault N, Manach C, Hercberg S, et al. Dietary intake of 337 polyphenols in French adults. Am J Clin Nutr. 2011;93:1220–8.PubMedCrossRef

Title: Role of a polyphenol-enriched preparation on chemoprevention of mammary carcinoma through cancer stem cells and inflammatory pathways modulation
Authors: Tri Vuong
Jean-François Mallet
Maria Ouzounova
Sam Rahbar
Hector Hernandez-Vargas
Zdenko Herceg
Chantal Matar
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Translational Medicine / Issue 1/2016
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-016-0770-7

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Role of a polyphenol-enriched preparation on chemoprevention of mammary carcinoma through cancer stem cells and inflammatory pathways modulation

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2016

LRG1 downregulation in allergic airway disorders and its expression in peripheral blood and tissue cells

The fibrolytic potentials of vitamin D and thymoquinone remedial therapies: insights from liver fibrosis established by CCl4 in rats

Pulsed high-dose dexamethasone modulates Th1-/Th2-chemokine imbalance in immune thrombocytopenia

Microbiota and neurologic diseases: potential effects of probiotics

Paracrine effects of TLR4-polarised mesenchymal stromal cells are mediated by extracellular vesicles

Bortezomib-mediated downregulation of S-phase kinase protein-2 (SKP2) causes apoptotic cell death in chronic myelogenous leukemia cells

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page