A peptide derived from alpha-fetoprotein inhibits the proliferation induced by estradiol in mammary tumor cells in culture

Abstract

This study was aimed to obtain additional information on the activity of a cyclized 9-amino acid peptide (cP) containing the active site of alpha fetoprotein, which inhibits the estrogen-stimulated proliferation of tumor cells in culture and of xenografts in immunodeficient mice. Breast cancer cells cultured in the presence of 2 nM estradiol were exposed to cP for different periods and their proliferation, estradiol binding parameters, clustering tendency and expression of E-cadherin and p21Cip1 were analyzed by biochemical and cell biology methods. The proliferation of MCF7 cells was significantly decreased by the addition of 2 μg/ml cP to the medium. cP did not increase cell death rate nor alter the number of binding sites for estradiol nor the endogenous aromatase activity of MCF7 cells. cP also decreased the proliferation of estrogen-dependent ZR75-1 cells but had no effect on estrogen-independent MDA-MB-231 cells. An increased nuclear p21Cip1 expression detected after cP treatment suggests that cP slows MCF7 cell proliferation via this regulator. We propose that cP could represent a novel breast cancer therapeutic agent whose mechanism of action is different from that of tamoxifen or of inhibitors of aromatase.

A Proposed Unified Mechanism for the Reduction of Human Breast Cancer Risk by the Hormones of Pregnancy

“…We avoided the use of steroid stimulation so as to preclude any trophic effects of steroids on the MCF-7 cells. In other work (36)(37)(38)(39), as well as in this report, we have shown that E 2 stimulates the growth of MCF-7 and T47D cells; it certainly does not inhibit proliferation. As shown clearly in Fig.…”

A cyclic peptide derived from α-fetoprotein inhibits the proliferative effects of the epidermal growth factor and estradiol in MCF7 cells

“…The peptide was effective slowing-down the proliferation of estrogen-dependent tumor cells, though not that of estrogen-independent MDA-MB231 cells. The cP did not increase the MCF7 cell death rate, nor altered cell E 2 binding capacity, nor modified cell aromatase activity (20).…”

“…Whereas in the proliferation studies under serum-free conditions, the cells were transferred to DMEM F12 containing ITS (insulin, transferrin, selenium), 3% hydroxyethylated starch (HAES), 0.5% human serum albumin, 50 U/ml penicillin and 50 μg/ml streptomycin. The E 2 -insensitive cell line MDA-MB231 (HTB-26; ATCC, USA), used for control studies, was cultured as described previously (20). In each of the experiments, the cells were incubated at 37˚C in a humidified incubator, under a 5% CO 2 atmosphere.…”

“…Recently, we demonstrated that E 2 -stimulated proliferation of mammary tumor cells was inhibited by the presence of the cyclic peptide in the culture medium (20). The peptide was effective slowing-down the proliferation of estrogen-dependent tumor cells, though not that of estrogen-independent MDA-MB231 cells.…”

Development of an Active Site Peptide Analog of α-Fetoprotein That Prevents Breast Cancer

“…AFPep does neither of these but does interfere with the phosphorylation of the ER, particularly at Ser 118 (64) but not at Ser 167 or Ser 104 (62). Unlike tamoxifen, AFPep does not alter the number of binding sites or their affinity for radiolabled estrogen (65,67,68 (67). AFPep interfered markedly with the regulation of mitogen-activated protein kinase (MAPK) by activated c-erbB2; it showed no effect on estrogen-stimulated release of matrix metalloproteinases 2 and 9 (69).…”