Genes & Nutrition

, Volume 8, Issue 1, pp 79–90

The soybean peptide lunasin promotes apoptosis of mammary epithelial cells via induction of tumor suppressor PTEN: similarities and distinct actions from soy isoflavone genistein

  • John Mark P. Pabona
  • Bhuvanesh Dave
  • Ying Su
  • Maria Theresa E. Montales
  • Ben O. de Lumen
  • Elvira G. de Mejia
  • Omar M. Rahal
  • Rosalia C. M. Simmen
Research Paper


Breast cancer is the leading cause of cancer deaths in women. Diet and lifestyle are major contributing factors to increased breast cancer risk. While mechanisms underlying dietary protection of mammary tumor formation are increasingly elucidated, there remains a dearth of knowledge on the nature and precise actions of specific bioactive components present in foods with purported health effects. The 43-amino acid peptide lunasin (LUN) is found in soybeans, is bioavailable similar to the isoflavone genistein (GEN), and thus may mediate the beneficial effects of soy food consumption. Here, we evaluated whether LUN displays common and distinct actions from those of GEN in non-malignant (mouse HC11) and malignant (human MCF-7) mammary epithelial cells. In MCF-7 cells, LUN up-regulated tumor suppressor phosphatase and tensin homolog deleted in chromosome ten (PTEN) promoter activity, increased PTEN transcript and protein levels and enhanced nuclear PTEN localization, similar to that shown for GEN in mammary epithelial cells. LUN-induced cellular apoptosis, akin to GEN, was mediated by PTEN, but unlike that for GEN, was p53-independent. LUN promoted E-cadherin and β-catenin non-nuclear localization similar to GEN, but unlike GEN, did not influence the proliferative effects of oncogene Wnt1 on HC11 cells. Further, LUN did not recapitulate GEN inhibitory effects on expansion of the cancer stem-like/progenitor population in MCF-7 cells. Results suggest the concerted actions of GEN and LUN on cellular apoptosis for potential mammary tumor preventive effects and highlight whole food consumption rather than intake of specific dietary supplements with limited biological effects for greater health benefits.


Lunasin Genistein Soy Apoptosis PTEN Mammary epithelial Breast cancer 


  1. Anastasius N, Boston S, Lacey M, Storing N, Whitehead SA (2009) Evidence that low dose, long-term genistein treatment inhibits oestradiol-stimulated growth in MCF-7 cells by down-regulation of the PI3-kinase/Akt signalling pathway. J Steroid Biochem Mol Biol 116:50–55PubMedCrossRefGoogle Scholar
  2. Andrade JE, Twaddle NC, Helferich WG, Doerge DR (2010) Absolute availability of isoflavones from soy protein isolate-containing food in female BALB/c mice. J Agric Food Chem 58:4529–4536PubMedCrossRefGoogle Scholar
  3. Boggs DA, Palmer JR, Wise LA, Spiegelman D, Stampfer MJ, Adams-Campbell LL, Rosenberg L (2010) Fruit and vegetable intake in relation to the risk of breast cancer in the Black Women’s health study. Am J Epidemiol 172:1268–1279PubMedCrossRefGoogle Scholar
  4. Boué SM, Tilghman SL, Elliot S, Zimmerman MC, Williams KY, Payton-Stewart F et al (2009) Identification of glycinol in elicited soybean (Glycine Max). Endocrinology 150:2446–2453PubMedCrossRefGoogle Scholar
  5. Caan BJ, Natarajan L, Parker B, Gold EB, Thomson C, Newman V, Rock CL, Pu M, Al-Delaimy W, Pierce JP (2011) Soy food consumption and breast cancer prognosis. Cancer Epidemiol Biomarkers Prev 20:854–858PubMedCrossRefGoogle Scholar
  6. Chiesa G, Rigamonti E, Lovati MR, Disconzi E, Soldati S, Sacco MG, Cato EM, Patton V et al (2008) Reduced mammary tumor progression in a transgenic mouse model fed an isoflavone-poor soy protein isolate. Mol Nutr Food Res 52:1121–1129PubMedCrossRefGoogle Scholar
  7. Colditz GA, Kaphingst KA, Hankinson SE, Rosner B (2012) Family history and risk of breast cancer: nurses’ health study. Breast Cancer Res Treat (in press)Google Scholar
  8. Dave D, Eason RR, Till SR, Geng Y, Velarde MC, Badger TM, Simmen RCM (2005) The soy isoflavone genistein promotes apoptosis in mammary epithelial cells by inducing the tumor suppressor PTEN. Carcinogenesis 26:1793–2103PubMedCrossRefGoogle Scholar
  9. De Mejia EG, Vάsconez M, de Lumen BO, Nelson R (2004) Lunasin concentration in different soybean genotypes, commercial soy protein, and isoflavone products. J Agric Food Chem 52:5882–5887CrossRefGoogle Scholar
  10. De Mejia EG, Wang W, Dia VP (2010) Lunasin, with an arginine-glycine-aspartic acid motif, causes apoptosis to L1210 leukemia cells by activation of caspase-3. Mol Nutr Food Res 54:406–414PubMedCrossRefGoogle Scholar
  11. Dia VP, Gonzalez de Mejia E (2011) Lunasin induces apoptosis and modifies the expression of genes associated with extracellular matrix and cell adhesion in human metastatic colon cancer cells. Mol Nutr Food Res 55:623–634PubMedCrossRefGoogle Scholar
  12. Dia VP, Mejia EG (2010) Lunasin promotes apoptosis in human colon cancer cells by mitochondrial pathway activation and induction of nuclear clusterin expression. Cancer Lett 295:44–53PubMedCrossRefGoogle Scholar
  13. Dia VP, Torres S, de Lumen BO, Erdman JW Jr, De Mejia EG (2009) Presence of lunasin in plasma of men after soy consumption. J Agric Food Chem 57(4):1260–1266PubMedCrossRefGoogle Scholar
  14. Dong JY, Qin LQ (2011) Soy isoflavones consumption and risk of breast cancer incidence or recurrence: a meta-analysis of prospective studies. Breast Cancer Res Treat 125:315–323PubMedCrossRefGoogle Scholar
  15. Fillmore CM, Kuperwasser C (2008) Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res 10:R25PubMedCrossRefGoogle Scholar
  16. Galvez AF, de Lumen BO (1999) A soybean cDNA encoding a chromatin-binding peptide inhibits mitosis of mammalian cells. Nat Biotech 17:495–500CrossRefGoogle Scholar
  17. Galvez AF, Chen N, Macasieb J, de Lumen BO (2001) Chemopreventive property of a soybean peptide (Lunasin) that binds to deacetylated histones and inhibits acetylation. Cancer Res 61:7473–7478PubMedGoogle Scholar
  18. Hsieh CC, Hernάndez-Ledesma B, de Lumen BO (2010a) Soybean peptide lunasin suppresses in vitro and in vivo 7, 12-dimethylbenz[a]anthracene-induced tumorigenesis. J Food Sci 75:311–316CrossRefGoogle Scholar
  19. Hsieh CC, Hernάndez-Ledesma B, Jeong HJ, Park JH, de Lumen BO (2010b) Complementary roles in cancer prevention: protease inhibitor makes the caner preventive peptide lunasin bioavailable. PLoS One 5:e8890PubMedCrossRefGoogle Scholar
  20. Hsieh CC, Hernάndez-Ledesma B, de Lumen BO (2010c) Lunasin, a novel seed peptide, sensitizes human breast cancer MDA-MB231 cells to aspirin-arrested cell cycle and induced apoptosis. Chem Biol Interact 186:127–134PubMedCrossRefGoogle Scholar
  21. Ikenoue T, Inoki K, Zhao B, Guan K-L (2008) Pten acetylation modulates its interaction with PDZ domain. Cancer Res 68:6908–6912PubMedCrossRefGoogle Scholar
  22. Irwin ML, Duggan C, Wang CY, Smith AW, McTiernan A, Baumgartner RN, Baumgartner KB, Bernstein L, Ballard-Barbash R (2011) Fasting C-peptide levels and death resulting from all causes and breast cancer: the health, eating, activity and lifestyle study. J Clin Oncol 29:47–53PubMedCrossRefGoogle Scholar
  23. Iwasaki M, Inoue M, Otani T, Sasazuki S, Kurahashi N, Miura T, Yamamoto S, Tsugane S, Japan Public Health Center-based Prospective Study Group (2008) Plasma isoflavones and subsequent risk of breast cancer among Japanese women: a nested case-control study from the Japan Public Health center-based prospective study group. J Clin Oncol 26:1677–1683PubMedCrossRefGoogle Scholar
  24. Jeong HJ, Jeong JB, Kim DS, de Lumen BO (2007) Inhibition of core histone acetylation by the cancer preventive peptide lunasin. J Agric Food Chem 55:632–637PubMedCrossRefGoogle Scholar
  25. Jeong HJ, Jeong JB, Hsieh CC, Hernάndez-Ledesma B, de Lumen BO (2010) Lunasin is prevalent in barley and is bioavailable and bioactive in in vivo and in vitro studies. Nutr Cancer 62:1113–1119PubMedCrossRefGoogle Scholar
  26. Jin Z, MacDonald RS (2002) Soy isoflavones increase latency of spontaneous mammary tumors in mice. J Nutr 132:3186–3190PubMedGoogle Scholar
  27. Kazi A, Daniel KG, Smith DM, Kumar NB, Dou QP (2003) Inhibition of the proteasome activity, a novel mechanism associated with the tumor cell apoptosis-inducing ability of genistein. Biochem Pharmacol 66:965–976PubMedCrossRefGoogle Scholar
  28. Key TJ, Appleby PN, Cairns BJ, Luben R, Dahm CC, Akbaraly T et al (2011) Dietary fat and breast cancer: comparison of results from food diaries and food-frequency questionnaires in the UK Dietary Cohort Consortium. Am J Clin Nutr 94:1043–1052PubMedCrossRefGoogle Scholar
  29. Korde LA, Wu AH, Fears T, Nomura AM, West DW, Kolonel LN, Pike MC, Hoover RN, Ziegler RG (2009) Childhood soy intake and breast cancer risk in Asian American women. Cancer Epidemiol Biomarkers Prev 18:1050–1059PubMedCrossRefGoogle Scholar
  30. Lam Y, Galvez A, de Lumen BO (2003) Lunasin suppresses E1A-mediated transformation of mammalian cells but does not inhibit growth of immortalized and established cancer cell lines. Nutr Cancer 47:88–94PubMedCrossRefGoogle Scholar
  31. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkati E, Skytthe A, Hemminki K (2000) Environmental and heritable factors in the causation of cancer-analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343:78–85PubMedCrossRefGoogle Scholar
  32. Ligibel J (2011) Obesity and breast cancer. Oncology 11:994–1000Google Scholar
  33. Montales MTE, Rahal OM, Kang J, Rogers T, Prior RL, Wu X, Simmen RCM (2012) 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 33:652–660PubMedCrossRefGoogle Scholar
  34. Okomura K, Mendoza M, Bachoo RM, DePinho RA, Cavenee WK, Furnan FB (2006) PCAF modulates PTEN activity. J Biol Chem 281:26562–26568CrossRefGoogle Scholar
  35. Orsulic S, Huber O, Aberle H, Arnold S, Kemler R (1999) E-cadherin binding prevents beta-catenin nuclear localization and beta-catenin/LEF-1-mediated transactivation. J Cell Sci 112:1237–1245PubMedGoogle Scholar
  36. Rahal OM, Simmen RCM (2010) PTEN and p53 cross-regulation induced by soy isoflavone genistein promotes mammary epithelial cell cycle arrest and lobuloalveolar differentiation. Carcinogenesis 31:1491–1500PubMedCrossRefGoogle Scholar
  37. Rahal OM, Simmen RCM (2011) Paracrine-acting adiponectin promotes mammary epithelial differentiation and synergizes with genistein to enhance transcriptional response to estrogen receptor β signaling. Endocrinology 152:3409–3421PubMedCrossRefGoogle Scholar
  38. Reeves PG, Nielsen FH, Fahey GC Jr (1993) AIN93 purified diets for laboratory rodents; final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr 123:1939–1951PubMedGoogle Scholar
  39. Rose DP, Vona-Davis L (2010) Interaction between menopausal status and obesity in affecting breast cancer risk. Maturitas 66:33–38PubMedCrossRefGoogle Scholar
  40. Shikany JM, Redden DT, Neuhouser ML, Chlebowski RT, Rohan TE, Simon MS, Liu S, Lane DS, Tinker L (2011) Dietary glycemic load, glycemic index, and carbohydrate and risk of breast cancer in the women’s health initiative. Nutr Cancer 63:899–907PubMedCrossRefGoogle Scholar
  41. Shu XO, Zheng Y, Cai H, Gu K, Chen Z, Zheng W, Lu W (2009) Soy food intake and breast cancer survival. JAMA 302:2437–2443PubMedCrossRefGoogle Scholar
  42. Siegel R, Naishadham D, Jemal A (2012) Cancer statistics 2012. CA Cancer J Clin 62:10–29PubMedCrossRefGoogle Scholar
  43. Silva-Sanchez C, Barba dela Rosa AP, Léon-Galván MF, de Lumen BO, de LéonRodriguez AG, de Mejia EG (2008) Bioactive peptides in amaranth (Amaranthus hypochondriacus) seed. J Agric Food Chem 56:1233–1240PubMedCrossRefGoogle Scholar
  44. Simmen RCM, Eason RR, Till SR, Chatman L Jr, Velarde MC, Geng Y, Korourian S, Badger TM (2005) Inhibition of NMU-induced mammary tumorigenesis by dietary soy. Cancer Lett 224:45–52PubMedCrossRefGoogle Scholar
  45. Su Y, Simmen RCM (2009) Soy isoflavone genistein upregulates epithelial adhesion molecule E-cadherin expression and attenuates β-catenin signaling in mammary epithelial cells. Carcinogenesis 30:331–339PubMedCrossRefGoogle Scholar
  46. Ullah MF, Ahmad A, Zubair H, Khan HY, Wang Z, Sarkar FH, Hadi SM (2011) Soy isoflavone genistein induces cell death in breast cancer cells through mobilization of endogenous copper ions and generation of reactive oxygen species. Mol Nutr Food Res 55:553–559PubMedCrossRefGoogle Scholar
  47. Vinall RL, Hwa K, Ghosh P, Pan CX, Lara PN Jr, de Vere White RW (2007) Combination treatment of prostate cancer cell lines with bioactive soy isoflavones and perifosine causes increased growth arrest and/or apoptosis. Clin Cancer Res 13:6204–6216PubMedCrossRefGoogle Scholar
  48. Virolle T, Adamson ED, Baron V, Birle D, Mercola D, Mustelin T, de Belle I (2001) The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling. Nat Cell Biol 3:1124–1128PubMedCrossRefGoogle Scholar
  49. Wang W, Bringe NA, Berhow MA, Gonzalez de Mejia EJ (2008) Beta-conglycinins among sources of bioactivities in hydrolysates of different soybean varieties that inhibit leukemia cells in vitro. J Agric Food Chem 56:4012–4020PubMedCrossRefGoogle Scholar
  50. Xiong SD, Yu K, Liu XH, Yin LH, Kirschenbaum A, Yao S et al (2009) Ribosome-inactivating proteins isolated from dietary bitter melon induce apoptosis and inhibit histone deacetylase-1 selectively in premalignant and malignant prostate cancer cells. Int J Cancer 125:774–782PubMedCrossRefGoogle Scholar
  51. Zhou JR, Yu L, Zhong Y, Nassr RL, Franke AA, Gaston SM, Blackburn GL (2002) Inhibition of orthotopic growth and metastasis of androgen-sensitive human prostate tumors in mice by bioactive soy components. Prostate 53:143–153PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • John Mark P. Pabona
    • 1
    • 2
  • Bhuvanesh Dave
    • 2
    • 3
  • Ying Su
    • 2
    • 4
  • Maria Theresa E. Montales
    • 1
    • 2
  • Ben O. de Lumen
    • 5
  • Elvira G. de Mejia
    • 6
  • Omar M. Rahal
    • 2
    • 7
  • Rosalia C. M. Simmen
    • 1
    • 2
    • 7
  1. 1.Physiology and BiophysicsUniversity of Arkansas for Medical SciencesLittle RockUSA
  2. 2.Arkansas Children’s Nutrition CenterLittle RockUSA
  3. 3.The Methodist Hospital Research InstituteHoustonUSA
  4. 4.Dana-Farber Cancer InstituteHarvard Medical SchoolBostonUSA
  5. 5.University of California BerkeleyBerkeleyUSA
  6. 6.University of Illinois at Urbana-ChampaignUrbanaUSA
  7. 7.Interdisciplinary Biomedical SciencesUniversity of Arkansas for Medical SciencesLittle RockUSA

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