) We have discovered that a small piece (amino acids 472-479) of the apha- fetoprotein molecule contains significant antiestrotrophic activity. We have synthesized this octapeptide (EMTPVNPG, henceforth referred to as P472) and have shown that it inhibits estrogen-stimulated growth of immature mouse uterus in vivo and estrogen-stimulated growth of T47D human breast cancer cells in culture. Moreover, it interferes with the trophic effects of tamoxifen on the mouse uterus. Mechanistically, P472 depletes phosphorylated mitogen-activated protein kinase (MAPK), an enzyme required for the phosphorylation of the estrogen receptor (ER), which is needed to fully operationalize the ER. The overall goal of this project is to develop this synthetic peptide as a novel, second-Iine endocrine agent for the treatment of breast cancer. Our hypothesis is that P472 will block estrogen-stimulated growth of human breast cancer in viva by a novel mechanism and will work in a complementary manner with current ER antagonist drugs such as tamoxifen.
The aims of this project are: 1. to demonstrate that P472 blocks estrogen-dependent growth of human breast cancer xenografts, including ER-positive tumors resistant to tamoxifen; 2. to pinpoint the site of action of P472 in the signal transduction pathway of MAPK; 3. to determine whether complementarity exists between P472 and tamoxifen when used in combination against human breast cancer cells growing either as a monolayer in culture or as a solid tumor xenograft in immune-deficient mice. We believe that we are working with a promising new agent that is antiestrotrophic, well tolerated and anti-oncotic for ER-positive breast cancer; that it will complement existing therapy, including a reduction in the untoward uterotrophic side effect of tamoxifen; and that ascertainment of its mechanism will increase our understanding of breast cancer growth as well as provide a new target for future drug development.
| Lin, Hung-Yun; Shih, Ai; Davis, Faith B et al. (2002) Resveratrol induced serine phosphorylation of p53 causes apoptosis in a mutant p53 prostate cancer cell line. J Urol 168:748-55 |
| Bennett, James A; Mesfin, Fassil B; Andersen, Thomas T et al. (2002) A peptide derived from alpha-fetoprotein prevents the growth of estrogen-dependent human breast cancers sensitive and resistant to tamoxifen. Proc Natl Acad Sci U S A 99:2211-5 |
| Mesfin, F B; Andersen, T T; Jacobson, H I et al. (2001) Development of a synthetic cyclized peptide derived from alpha-fetoprotein that prevents the growth of human breast cancer. J Pept Res 58:246-56 |
