A Synthetic Peptide Derived from Alpha-fetoprotein Inhibits the Estradiol-induced Proliferation of Mammary Tumor Cells in Culture through the Modulation of p21

  • Walter D. Sierralta
  • María J. Epuñan
  • José M. Reyes
  • Luis E. Valladares
  • Ana M. Pino
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 617)


A stable cyclized 9-mer peptide (cP) containing the active site of α-alpha fetoprotein (αFP) has been shown to be effective for prevention of estrogenstimulated tumor cell proliferation in culture or of xenographt growth in immunodeficient mice. cP does not block 17β-estradiol (E2) binding to its receptors, but rather appears to interfere with intracellular processing of the signal that supports growth. To obtain insight on that mechanism we studied the effect of cP on the proliferation of MCF-7 cells in culture. Proliferation in the presence of 2μM E2 is decreased up to 40% upon addition of 2μg ml-1 cP to the medium; the presence of cP did not increase cell death. cP reduced also the proliferation of estrogen-dependent ZR75-1 cells but had no effect on autonomous MDA-MB-231 cells. cP did not modify the number of binding sites for labeled E2 or affected cell death. We detected increased nuclear p21Cip1 immunoreactivity after cP treatment. Our results suggest that cP acts via p21Cip1 to slow the process of MCF-7 cells through the cycle.


MCF7 Cell Cyclic Peptide Human Breast Cancer Xenograft Wild Type MCF7 Cell Slowering Cell Cycle Progression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Sommer S, Fuqua SA (2001) Oestrogen receptor and breast cancer. Sem Cancer Biol 11:339–352.CrossRefGoogle Scholar
  2. 2.
    Tsai M, O’Malley BW (1994) Molecular mechanism of action of steroid/thyroid superfamily members. Ann Rev Biochem 63:451–486.PubMedCrossRefGoogle Scholar
  3. 3.
    Batistuzzo de Madeiros SR, Krey G, Hihi AK, et al. (1997) Functional interaction between the estrogen receptor and the transcription factor Sp1 regulate the estrogen-dependent transcriptional activity of the vitellogenin A1 promoter. J Biol Chem 272:18250–18260.CrossRefGoogle Scholar
  4. 4.
    Bates SE, Davidson NE, Valverius EM, et al. (1998) Expression of transforming growth factor-alpha and its messenger ribonucleic acid in human breast cancer: its regulation by estrogen and its posssible functional significance. Mol Endocrinol 2:543–555.CrossRefGoogle Scholar
  5. 5.
    Huynh H, Yang X, Pollak M (1996) Estradiol and antiestrogens regulate a growth inhibitory insulin-like growth factor binding protein 3 autocrine loop in human breast cancer cell. J Biol Chem 271:1016–1021.PubMedCrossRefGoogle Scholar
  6. 6.
    Kato S, Endoh H, Masuhiro Y, et al. (1995) Activation of the estrogen receptor through phosphorylation by mitogen-activated protein-kinase. Science 270:1491–1494.PubMedCrossRefGoogle Scholar
  7. 7.
    Simoncini T, Hafezi-Moghadam A, Brazil DP, et al. (2000) Interaction of estrogen receptor with the regulatory subunit of phophatidylinositol-3-OH kinase. Nature 407:538–541.PubMedCrossRefGoogle Scholar
  8. 8.
    Santen RJ, Song RX, MacPherson R, et al. (2002) The role of mitogen-activated protein (MAP) kinase in breast cancer. J Steroid Biochem Mol Biol 80:239–256.PubMedCrossRefGoogle Scholar
  9. 9.
    Levin ER (2002) Cellular functions of plasma membrane estrogen receptors. Steroids 67:471–475.PubMedCrossRefGoogle Scholar
  10. 10.
    Santen (2002) To block estrogen’s synthesis or action: that is the question. J Clin Endo Met 87:3007–3012.CrossRefGoogle Scholar
  11. 11.
    Gradishar WJ, Jordan VC (1997) Clinical potential of new antie-strogens. J Clin Oncol 15:840–852.PubMedGoogle Scholar
  12. 12.
    Jacobson HI, Thompson WD, Janerich DT (1989) Multiple births and maternal risk of breast cancer. Am J Epidemiol 129:865–873.PubMedGoogle Scholar
  13. 13.
    Jacobson HI, Bennet JA, Mizejewski GJ (1990) Inhibition of estrogen-dependent breast cancer growth by a reaction product of alpha-fetoprotein and estradiol. Cancer Res 50:415–420.PubMedGoogle Scholar
  14. 14.
    DeFreest LA, Mesfin FB, Joseph L, et al. (2004) Synthethic peptide derived from alpha-fetoprotein inhibits growth of human breast cancer: investigation of the pharmacophore and synthesis optimization. J Pept Res 63:409–419.PubMedCrossRefGoogle Scholar
  15. 15.
    Bennett JA, DeFreest L, Anaka I, et al. (2006) AFPep: an anti-breast cancer peptide that is orally active. Breast Cancer Res Treat 98:133–141.PubMedCrossRefGoogle Scholar
  16. 16.
    Doisneau-Sixou SF, Sergio CM, Carroll JS, et al. (2003) Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells. Endocrine-Related Cancer 10:179–186.PubMedCrossRefGoogle Scholar
  17. 17.
    Bennett JA, Mesfin FB, Andersen TT, et al. (2002) A peptide derived from α-fetoprotein prevents the growth of estrogen-dependent human breast cancers sensitive and resistant to tamoxifen. Proc Natl Acad Sci USA 99:2211–2215.PubMedCrossRefGoogle Scholar
  18. 18.
    Planas-Silva MD, Weinberg RA (1997) Estrogen-dependent cyclin E-Cdk2 activation through p21 redistribution. Mol Cell Biol 17:4059–4069.PubMedGoogle Scholar
  19. 19.
    Margueron R, Licznar A, Lazennec G, et al. (2003) Oestrogen receptor α increases p21 WAF1/CIP1 gene expression and the antiproliferative activity of histone acetylase inhibitors in human breast cancer cells. J Endocrinol 179:41–53.PubMedCrossRefGoogle Scholar
  20. 20.
    Hattinger CM, Jochemsen AG, Tanke HJ, et al. (2002) Induction of p21 mRNA synthesis after short-wavelength UV light visualized in individual cells by RNA FISH. J Histochem Cytochem 50:81–89.PubMedGoogle Scholar
  21. 21.
    Parikh RR, Gildener-Leapman N, Narendran A, et al. (2005) Prevention of n-methyl-N-nitrosourea-induced breast cancer by alpha-fetoprotein (AFP)-derived eptide, a peptide derived from the active site of AFP. Clin Cancer Res 11:8512–8520.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Walter D. Sierralta
    • 1
  • María J. Epuñan
  • José M. Reyes
  • Luis E. Valladares
  • Ana M. Pino
  1. 1.INTA-Universidad de ChileSantiagoChile

Personalised recommendations