Effects of progestins, estrogens, and antihormones on growth and lactate dehydrogenase in the human breast cancer cell line T47D.
We have previously reported progestin stimulation of growth and lactate dehydrogenase (LDH) in the human breast cancer cell line T47D. Our further findings now show that growth stimulation by progestins occurs in a dose-responsive manner at physiological concentrations and is inhibited by the antiprogestin RU486. 17 beta-Estradiol (E2) also stimulates proliferation and LDH, and these stimulations are inhibited by tamoxifen. In addition, tamoxifen alone slightly stimulates proliferation. Surprisingly, RU486 also inhibits stimulation by E2. Thus, RU486 acts not only as an antiprogestin, but also as an antiestrogen. While combined promegestone (R5020) and E2 substantially stimulate proliferation, when RU486 is added to this combination it does not further inhibit, but leads to enhanced stimulation. However, the same addition of RU486 to combined E2 and R5020 diminishes LDH stimulation. This suggests that LDH stimulation and growth stimulation are dissociated. Finally, tamoxifen inhibits growth stimulation by combined R5020 and E2, but addition of the antiprogestin RU486 to this combination does not lead to a further inhibition of proliferation. Even so, this same combination reduces LDH levels to control values, further suggesting that stimulation of growth and LDH are dissociated. All of these findings occurred in the absence of the estrogenic pH indicator phenol red. These results emphasize the potential of LDH as an end point for studying the mechanism of female steroid hormone action. They also reveal antiestrogenic activity in RU486. Further, they shed light on the interaction among estrogens, progestins, antiestrogens, and antiprogestins in their effects on growth. Further understanding of this complex interplay may be helpful in treatment of human breast cancer.
Hissom
J R
JR
Department of Biochemistry, Marshall University School of Medicine, Huntington, West Virginia 25704.
Bowden
R T
RT
Moore
M R
MR
D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D004963:Estrenes / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism*; D015735:Mifepristone; D011372:Progestins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011397:Promegestone / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004963:Estrenes; D004967:Estrogens; D006727:Hormone Antagonists; D011372:Progestins; D015735:Mifepristone; D011397:Promegestone; D007770:L-Lactate Dehydrogenase