Involvement of the polyamine pathway in antiestrogen-induced growth inhibition of human breast cancer.
Recent evidence indicates that the antiestrogen tamoxifen (TAM) may inhibit breast cancer cell proliferation, at least in part, through suppression of the polyamine (PA) pathway. To directly test this hypothesis, we evaluated the effect of TAM administration on ornithine decarboxylase (ODC) activity, the rate-limiting enzyme in PA synthesis, as well as cellular PA levels in the hormone-responsive MCF-7 breast cancer cell line in culture. In detailed time course studies, we observed that TAM significantly inhibited the rise in ODC activity observed in control cells following a medium change. Chronic treatment with escalating amounts of TAM caused a dose-related decrease in tumor pools of putrescine and spermidine, while spermine levels were unaffected. The TAM effects on ODC activity and PA pools were reversible with exogenous estradiol administration. However, addition of putrescine to TAM-treated cells did not result in a reversal of the antiproliferative effect of TAM, despite repletion of cellular PA pools. Administration of TAM to the hormone-independent MDA-MB-231 breast cancer cell line did not suppress ODC activity or cellular PA levels despite induction, at high concentrations, of an estradiol-irreversible inhibition of proliferation. We conclude that, in the hormone-responsive MCF-7 breast cancer cell line, TAM causes a significant suppression of the PA pathway, the relation of which, if any, to its antiproliferative action remains obscure. This effect seems to be mediated through the estrogen receptor and does not appear to be a nonspecific consequence of inhibition of cell proliferation.
Cohen
F J
FJ
Department of Medicine, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey 17033.
Manni
A
A
Glikman
P
P
Bartholomew
M
M
Demers
L
L
D015317:Biogenic Polyamines / Q000378:metabolism*; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D009955:Ornithine Decarboxylase / Q000378:metabolism; D011073:Polyamines / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D015317:Biogenic Polyamines; D011073:Polyamines; D013629:Tamoxifen; D004958:Estradiol; D009955:Ornithine Decarboxylase