Dietary estrogens stimulate human breast cells to enter the cell cycle.
It has been suggested that dietary estrogens neutralize the effect of synthetic chemicals that mimic the effects of estrogen (i.e., xenoestrogens, environmental estrogens). Genistein, a dietary estrogen, inhibits the growth of breast cancer cells at high doses but additional studies have suggested that at low doses, genistein stimulates proliferation of breast cancer cells. Therefore, if dietary estrogens are estrogenic at low doses, one would predict that they stimulate estrogen-receptor positive breast cancer cells to enter the cell cycle. Genistein and the fungal toxin zearalenone were found to increase the activity of cyclin dependent kinase 2 (Cdk2) and cyclin D1 synthesis and stimulate the hyperphosphorylation of the retinoblastoma susceptibility gene product pRb105 in MCF-7 cells. The steroidal antiestrogen ICI 182,780 suppressed dietary estrogen-mediated activation of Cdk2. Dietary estrogens not only failed to suppress DDT-induced Cdk2 activity, but were found to slightly increase enzyme activity. Both zearalenone and genistein were found to stimulate the expression of a luciferase reporter gene under the control of an estrogen response element in MVLN cells. Our findings are consistent with a conclusion that dietary estrogens at low concentrations do not act as antiestrogens, but act like DDT and estradiol to stimulate human breast cancer cells to enter the cell cycle.
Dees
C
C
Health Sciences Research Division, Oak Ridge National Laboratory, Tennessee, USA. genase@aol.com
Foster
J S
JS
Ahamed
S
S
Wimalasena
J
J
D001940:Breast / Q000166:cytology* / Q000187:drug effects*; D001943:Breast Neoplasms / Q000209:etiology / Q000378:metabolism; D042846:CDC2-CDC28 Kinases; D002273:Carcinogens / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects*; D019938:Cyclin D1; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis; D004032:Diet / Q000009:adverse effects*; D004782:Environmental Health; D004789:Enzyme Activation / Q000187:drug effects; D004968:Estrogens, Non-Steroidal / Q000633:toxicity*; D005260:Female; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D009376:Neoplasms, Hormone-Dependent / Q000209:etiology / Q000378:metabolism; D015513:Oncogene Proteins / Q000096:biosynthesis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D012307:Risk Factors; D014407:Tumor Cells, Cultured
D002273:Carcinogens; D016213:Cyclins; D004968:Estrogens, Non-Steroidal; D015513:Oncogene Proteins; D011960:Receptors, Estrogen; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases