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Department of Medicine, University of Colorado Health Sciences Center Denver, Colorado 80262
Department of Pathology Denver, Colorado 80262
Department of Cell Biology, Baylor College of Medicine Houston, Texas 77030
Address requests for reprints to: Dr. Kathryn B. Horwitz, Department of Medicine, Box B151, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, Colorado 80262.
Abstract
We have used AB-52, a monoclonal antibody which recognizes both the A (94,000 daltons) and B (120,000 daltons) proteins of human progesterone receptors (hPR), and hPR-50, a PR complementary DNA probe isolated from a T47D-pcD library, to study the structure and hormonal regulation of the hPR mRNAs and proteins in human breast cancer cells. RNA blot hybridization analysis of poly(A+) RNA shows that T47DCO, an estrogen resistant human breast tumor cell line in which PR are constitutively expressed, contain at least six PR mRNAs ranging in size from 2.5 to 11.4 kilobases. All six are mature cytoplasmic messages that are also present in normal human endometrium and in PR-positive MCF-7 breast cancer cells, but not in PR-negative cells. Using hPR-50 RNA synthesized in vitro as a 1.3 kilobase standard, we calculate that MCF-7 cells contain approximately 16 message molecules per cell which are increased to approximately 45 by estradiol treatment; T47DCO cells contain approximately 90 message molecules per cell constitutively expressed. Treatment of T47DCO cells with progesterone leads to down-regulation of immunoreactive A- and B-receptors in the first 8–12 h, followed by their replenishment during the next 48 h. In parallel, hPR message levels initially decrease and then return to pretreatment levels. The synthetic progestin R5020 chronically down-regulates A- and B-receptors; the proteins are profoundly suppressed for at least 48 h, while PR mRNAs fall to less than 15% of control. However, with both hormones, parallel changes in protein and message levels are observed, suggesting that progestational agonists autoregulate the levels of their own receptors by inhibiting transcription of the PR gene. Antagonists appear to have different effects. With the antiprogestin RU 486 there is discordance between hPR protein and message levels which may be due to an ineffective inhibitory interaction between the antagonistoccupied receptors and PR genes, thereby disrupting the negative feedback loop.
FOOTNOTES
These studies were funded by the Cancer League of Colorado and National Research Service Award CA-08271 (to L.L.W.); by NIH Grants HD-08188 and HD-07857 (to B.W.O.); and by NIH Grant CA-26869, the National Science Foundation Grant PCM-831863, and the National Foundation for Cancer Research (to K.B.H.)
Received for publication September 28, 1987. Accepted for publication October 28, 1987.
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