Effect of cadmium on estrogen receptor levels and estrogen-induced responses in human breast cancer cells.
The effects of cadmium on estrogen receptor and other estrogen-regulated genes in the human breast cancer cell line MCF-7 were studied. Treatment of MCF-7 cells with 1 microM cadmium decreased the level of estrogen receptor 58%. Cadmium induced a parallel decrease in estrogen receptor mRNA (62%). Progesterone receptor levels increased 3.2-fold after cadmium treatment. This induction was blocked by the anti-estrogen ICI-164,384. Progesterone receptor mRNA was also increased by cadmium, as well as cathepsin D mRNA. An in vitro nuclear transcription run-on assay showed that cadmium increased the transcription of the progesterone receptor and pS2 genes and decreased transcription of the estrogen receptor gene. These are not general effects of heavy metals, as zinc, 25 and 100 microM, did not affect progesterone receptor protein and mRNA levels. Cadmium stimulated pS2 and progesterone receptor mRNAs in a clone of MDA-MB-231 cells transfected with the human estrogen receptor, but had no effect in MDA-MB-231 cells transfected with antisense estrogen receptor. Cadmium also stimulated an estrogen response element in transient transfection experiments. These data suggest that the effects of cadmium are mediated by the estrogen receptor independent of estradiol. In addition to its effect on gene expression, cadmium induced the growth of MCF-7 cells 5.6-fold.
Garcia-Morales
P
P
Department of Biochemistry and Molecular Biology, Vincent T. Lombardi Cancer Research Center, Georgetown University, Washington, D.C. 20007.
Saceda
M
M
Kenney
N
N
Kim
N
N
Salomon
D S
DS
Gottardis
M M
MM
Solomon
H B
HB
Sholler
P F
PF
Jordan
V C
VC
Martin
M B
MB
D001943:Breast Neoplasms / Q000378:metabolism*; D002104:Cadmium / Q000494:pharmacology*; D002402:Cathepsin D / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D009363:Neoplasm Proteins / Q000096:biosynthesis; D011506:Proteins; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D000071163:Trefoil Factor-1; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D009363:Neoplasm Proteins; D011506:Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D002104:Cadmium; D015500:Chloramphenicol O-Acetyltransferase; D002402:Cathepsin D