BreastDefend™ prevents breast-to-lung cancer metastases in an orthotopic animal model of triple-negative human breast cancer

Jiang,Jiahua; Thyagarajan-Sahu,Anita; Loganathan,Jagadish; Eliaz,Isaac; Terry,Colin; Sandusky,George E.; Sliva,Daniel

doi:10.3892/or.2012.1936

BreastDefend™ prevents breast-to-lung cancer metastases in an orthotopic animal model of triple-negative human breast cancer

Authors:
- Jiahua Jiang
- Anita Thyagarajan-Sahu
- Jagadish Loganathan
- Isaac Eliaz
- Colin Terry
- George E. Sandusky
- Daniel Sliva
View Affiliations

Affiliations: Cancer Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, IN 46202, USA, Amitabha Medical Clinic and Healing Center, Sebastopol, CA, USA, Department of Pathology Indiana University School of Medicine, Indianapolis, IN, USA
Published online on: July 26, 2012 https://doi.org/10.3892/or.2012.1936
Pages: 1139-1145
Copyright: © Jiang et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

We have recently demonstrated that a natural dietary supplement BreastDefend (BD), which contains extracts from medicinal mushrooms (Coriolus versicolor, Ganoderma lucidum, Phellinus linteus), medicinal herbs (Scutellaria barbata, Astragalus membranaceus, Curcuma longa), and purified biologically active nutritional compounds (diindolylmethane and quercetin), inhibits proliferation and metastatic behavior of MDA-MB-231 invasive human breast cancer cells in vitro. In the present study, we evaluated whether BD suppresses growth and breast-to lung cancer metastasis in an orthotopic model of human breast cancer cells implanted in mice. Oral application of BD (100 mg/kg of body weight for 4 weeks) by intragastric gavage did not affect body weight or activity of liver enzymes and did not show any sign of toxicity in liver, spleen, kidney, lung and heart tissues in mice. Moreover, BD significantly decreased the change in tumor volume over time compared to the control group (p=0.002). BD treatment also markedly decreased the incidence of breast-to-lung cancer metastasis from 67% (control) to 20% (BD) (p<0.05) and the number of metastases from 2.8 (0.0, 48.0) in the control group to 0.0 (0.0, 14.2) in the BD treatment group (p<0.05). Finally, anti-metastatic activity of BD in vivo was further confirmed by the downregulation of expression of PLAU (urokinase plasminogen activator, uPA) and CXCR4 (C-X-C chemokine receptor-4) genes in breast tumors. In conclusion, BD may be considered as a biological therapeutic agent against invasive breast cancers.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics. CA Cancer J Clin. 60:277–300. 2010.
3	Aggarwal BB and Shishodia S: Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol. 71:1397–1421. 2006. View Article : Google Scholar : PubMed/NCBI
4	Velicer CM and Ulrich CM: Vitamin and mineral supplement use among US adults after cancer diagnosis: a systematic review. J Clin Oncol. 26:665–673. 2008. View Article : Google Scholar : PubMed/NCBI
5	Miller MF, Bellizzi KM, Sufian M, Ambs AH, Goldstein MS and Ballard-Barbash R: Dietary supplement use in individuals living with cancer and other chronic conditions: a population-based study. J Am Diet Assoc. 108:483–494. 2008. View Article : Google Scholar : PubMed/NCBI
6	Jiang J, Wojnowski R, Jedinak A and Sliva D: Suppression of proliferation and invasive behavior of human metastatic breast cancer cells by dietary supplement BreastDefend. Integr Cancer Ther. 10:192–200. 2011. View Article : Google Scholar : PubMed/NCBI
7	Ho CY, Kim CF, Leung KN, Fung KP, Tse TF, Chan H and Lau CB: Differential anti-tumor activity of Coriolus versicolor (Yunzhi) extract through p53- and/or Bcl-2-dependent apoptotic pathway in human breast cancer cells. Cancer Biol Ther. 4:638–644. 2005.PubMed/NCBI
8	Jiang J, Slivova V and Sliva D: Ganoderma lucidum inhibits proliferation of human breast cancer cells by downregulation of estrogen receptor and NF-kappaB signaling. Int J Oncol. 29:695–703. 2006.
9	Thyagarajan A, Jiang J, Hopf A, Adamec J and Sliva D: Inhibition of oxidative stress-induced invasiveness of cancer cells by Ganoderma lucidum is mediated through the suppression of interleukin-8 secretion. Int J Mol Med. 18:657–664. 2006.PubMed/NCBI
10	Sliva D: Suppression of cancer invasiveness by dietary compounds. Mini Rev Med Chem. 8:677–688. 2008. View Article : Google Scholar : PubMed/NCBI
11	Bui-Xuan NH, Tang PM, Wong CK and Fung KP: Photo-activated pheophorbide-a, an active component of Scutellaria barbata, enhances apoptosis via the suppression of ERK-mediated autophagy in the estrogen receptor-negative human breast adenocarcinoma cells MDA-MB-231. J Ethnopharmacol. 131:95–103. 2010. View Article : Google Scholar
12	Ye MN and Chen HF: Effects of Astragalus injection on proliferation of basal-like breast cancer cell line MDA-MB-468. Zhong Xi Yi Jie He Xue Bao. 6:399–404. 2008.PubMed/NCBI
13	Shao ZM, Shen ZZ, Liu CH, Sartippour MR, Go VL, Heber D and Nguyen M: Curcumin exerts multiple suppressive effects on human breast carcinoma cells. Int J Cancer. 98:234–240. 2002. View Article : Google Scholar : PubMed/NCBI
14	Bachmeier B, Nerlich AG, Iancu CM, Cilli M, Schleicher E, Vené R, Dell’Eva R, et al: The chemopreventive polyphenol Curcumin prevents hematogenous breast cancer metastases in immunodeficient mice. Cell Physiol Biochem. 19:137–152. 2007. View Article : Google Scholar : PubMed/NCBI
15	Schlachterman A, Valle F, Wall KM, Azios NG, Castillo L, Morell L, Washington AV, et al: Combined resveratrol, quercetin, and catechin treatment reduces breast tumor growth in a nude mouse model. Transl Oncol. 1:19–27. 2008. View Article : Google Scholar : PubMed/NCBI
16	Castillo-Pichardo L, Martínez-Montemayor MM, Martínez JE, Wall KM, Cubano LA and Dharmawardhane S: Inhibition of mammary tumor growth and metastases to bone and liver by dietary grape polyphenols. Clin Exp Metastasis. 26:505–516. 2009. View Article : Google Scholar : PubMed/NCBI
17	Hsu EL, Chen N, Westbrook A, Wang F, Zhang R, Taylor RT and Hankinson O: CXCR4 and CXCL12 down-regulation: a novel mechanism for the chemoprotection of 3,3′-diindolylmethane for breast and ovarian cancers. Cancer Lett. 265:113–123. 2008.PubMed/NCBI
18	Ahmad A, Kong D, Wang Z, Sarkar SH, Banerjee S and Sarkar FH: Down-regulation of uPA and uPAR by 3,3′-diindolylmethane contributes to the inhibition of cell growth and migration of breast cancer cells. J Cell Biochem. 108:916–925. 2009.
19	Elliott BE, Meens JA, SenGupta SK, Louvard D and Arpin M: The membrane cytoskeletal crosslinker ezrin is required for metastasis of breast carcinoma cells. Breast Cancer Res. 7:R365–R373. 2005. View Article : Google Scholar : PubMed/NCBI
20	Gelmann EP, Thompson EW and Sommers CL: Invasive and metastatic properties of MCF-7 cells and rasH-transfected MCF-7 cell lines. Int J Cancer. 50:665–669. 1992. View Article : Google Scholar : PubMed/NCBI
21	Xue C, Plieth D, Venkov C, Xu C and Neilson EG: The gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis. Cancer Res. 63:3386–3394. 2003.PubMed/NCBI
22	Vanzulli SI, Soldati R, Meiss R, Colombo L, Molinolo AA and Lanari C: Estrogen or antiprogestin treatment induces complete regression of pulmonary and axillary metastases in an experimental model of breast cancer progression. Carcinogenesis. 26:1055–1063. 2005. View Article : Google Scholar
23	Zhao J, Ni H, Ma Y, Dong L, Dai J, Zhao F, Yan X, et al: TIP30/CC3 expression in breast carcinoma: relation to metastasis, clinicopathologic parameters, and P53 expression. Hum Pathol. 38:293–298. 2007. View Article : Google Scholar : PubMed/NCBI
24	Aggarwal BB, Shishodia S, Takada Y, Banerjee S, Newman RA, Bueso-Ramos CE and Price JE: Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice. Clin Cancer Res. 11:7490–7498. 2005. View Article : Google Scholar : PubMed/NCBI
25	Lee WJ, Chen WK, Wang CJ, Lin WL and Tseng TH: Apigenin inhibits HGF-promoted invasive growth and metastasis involving blocking PI3K/Akt pathway and beta 4 integrin function in MDA-MB-231 breast cancer cells. Toxicol Appl Pharmacol. 226:178–191. 2008. View Article : Google Scholar : PubMed/NCBI
26	Ishihara Y, Iijima H and Matsunaga K: Contribution of cytokines on the suppression of lung metastasis. Biotherapy. 11:267–275. 1998. View Article : Google Scholar : PubMed/NCBI
27	Maehara Y, Tsujitani S, Saeki H, Oki E, Yoshinaga K, Emi Y, Morita M, et al: Biological mechanism and clinical effect of protein-bound polysaccharide K (KRESTIN(^®)): review of development and future perspectives. Surg Today. 42:8–28. 2012. View Article : Google Scholar
28	Han SB, Lee CW, Jeon YJ, Hong ND, Yoo ID, Yang KH and Kim HM: The inhibitory effect of polysaccharides isolated from Phellinus linteus on tumor growth and metastasis. Immunopharmacology. 41:157–164. 1999. View Article : Google Scholar : PubMed/NCBI
29	Lee HJ, Lee HJ, Lim ES, Ahn KS, Shim BS, Kim HM, Gong SJ, et al: Cambodian Phellinus linteus inhibits experimental metastasis of melanoma cells in mice via regulation of urokinase type plasminogen activator. Biol Pharm Bull. 28:27–31. 2005.PubMed/NCBI
30	Kimura Y, Taniguchi M and Baba K: Antitumor and antimetastatic effects on liver of triterpenoid fractions of Ganoderma lucidum: mechanism of action and isolation of an active substance. Anticancer Res. 22:3309–3318. 2002.PubMed/NCBI
31	Nonaka Y, Ishibashi H, Nakai M, Shibata H, Kiso Y and Abe S: Effects of the antlered form of Ganoderma lucidum on tumor growth and metastasis in cyclophosphamide-treated mice. Biosci Biotechnol Biochem. 72:1399–1408. 2008.PubMed/NCBI
32	Chen NH, Liu JW and Zhong JJ: Ganoderic acid T inhibits tumor invasion in vitro and in vivo through inhibition of MMP expression. Pharmacol Rep. 62:150–163. 2010. View Article : Google Scholar : PubMed/NCBI
33	Kim EJ, Shin M, Park H, Hong JE, Shin HK, Kim J, Kwon DY, et al: Oral administration of 3,3′-diindolylmethane inhibits lung metastasis of 4T1 murine mammary carcinoma cells in BALB/c mice. J Nutr. 139:2373–2379. 2009.
34	Sliva D, Jedinak A, Kawasaki J, Harvey K and Slivova V: Phellinus linteus suppresses growth, angiogenesis and invasive behaviour of breast cancer cells through the inhibition of AKT signalling. Br J Cancer. 98:1348–1356. 2008. View Article : Google Scholar
35	Han B, Nakamura M, Mori I, Nakamura Y and Kakudo K: Urokinase-type plasminogen activator system and breast cancer (review). Oncol Rep. 14:105–112. 2005.PubMed/NCBI
36	Frandsen TL, Holst-Hansen C, Nielsen BS, Christensen IJ, Nyengaard JR, Carmeliet P and Brünner N: Direct evidence of the importance of stromal urokinase plasminogen activator (uPA) in the growth of an experimental human breast cancer using a combined uPA gene-disrupted and immunodeficient xenograft model. Cancer Res. 61:532–537. 2001.
37	Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, et al: Involvement of chemokine receptors in breast cancer metastasis. Nature. 410:50–56. 2001.PubMed/NCBI
38	Liang Z, Yoon Y, Votaw J, Goodman MM, Williams L and Shim H: Silencing of CXCR4 blocks breast cancer metastasis. Cancer Res. 65:967–671. 2005.PubMed/NCBI
39	Ma WF, Du J, Fu LP, Fang R, Chen HY and Cai SH: Phenotypic knockout of CXCR4 by a novel recombinant protein TAT/54R/KDEL inhibits tumors metastasis. Mol Cancer Res. 7:1613–1621. 2009. View Article : Google Scholar : PubMed/NCBI
40	Kim J, Thorne SH, Sun L, Huang B and Mochly-Rosen D: Sustained inhibition of PKCα reduces intravasation and lung seeding during mammary tumor metastasis in an in vivo mouse model. Oncogene. 30:323–333. 2011.
41	Giricz O, Calvo V, Pero SC, Krag DN, Sparano JA and Kenny PA: GRB7 is required for triple-negative breast cancer cell invasion and survival. Breast Cancer Res Treat. Oct 18–2011.(Epub ahead of print).
42	Cleator S, Heller W and Coombes RC: Triple-negative breast cancer: therapeutic options. Lancet Oncol. 8:235–244. 2007. View Article : Google Scholar : PubMed/NCBI