Demonstration of mixed properties of RU486 in progesterone receptor (PR)-transfected MDA-MB-231 cells: a model for studying the functions of progesterone analogues.

Abstract

Progesterone antagonist RU486 (mifepristone) has been implicated for many anti-neoplastic and obstetrical applications. But the compound has demonstrated undesired agonist-like effect depending on cell, tissue and species studied. Using PR-transfected breast cancer cells MDA-MB-231, this report describes the similarities and differences between progesterone- and RU486-mediated effects on cell growth, cell differentiation and, at the molecular level, on the activation of p44/p42 MAP kinases (MAPK). Like progesterone, RU486 inhibited cells growth by arresting the cells in G0/G1 phase of the cell cycle. In contrast to progesterone that induced cell spreading, RU486 induced a multipolar, stellate morphology. RU486-treated cells showed no increase of stress fibers, nor was there any increase of focal adhesions as progesterone-treated cells did. Furthermore, despite of the fact that both compounds inhibited cell growth, RU486 significantly stimulated the activation of p44/p42 MAP kinases whereas progesterone markedly inhibited the activation. Nonetheless, the effects of RU486 were PR-mediated and RU486 was able to antagonize the effect of progesterone on cell growth and focal adhesion. In conclusion, RU486 can act not only as a progesterone antagonist, a progesterone agonist but also induced morphological and molecular changes that were distinct from progesterone-mediated effects in PR-transfected MDA-MB-231 cells. The non-progesterone-like effect of RU486 may be mediated through a pathway that is different from the progesterone-mediated pathway, or it is the result of a blockade of certain critical step(s) in the progesterone-mediated pathway. In any case, undesired side effects of antiprogestin may create clinical complications. PR-transfected MDA-MB-231 breast cancer cells provide a model for studying the functions of progesterone analogues.

• Authors: V C Lin, S E Aw, E H Ng, E H Ng, M G Tan
• Journal: British journal of cancer (Br J Cancer) Vol. 85 Issue 12 Pg. 1978-86 (Dec 14 2001) ISSN: 0007-0920 [Print] England
• PMID: 11747343 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Gonanes
• Hormone Antagonists
• Receptors, Progesterone
• Recombinant Fusion Proteins
• Mifepristone
• Progesterone
• onapristone

Topics

• Breast Neoplasms (pathology)
• Cell Cycle (drug effects)
• Cell Division (drug effects)
• Cell Size (drug effects)
• Enzyme Activation (drug effects)
• Female
• Focal Adhesions (drug effects)
• Gonanes (pharmacology)
• Hormone Antagonists (pharmacology)
• Humans
• MAP Kinase Signaling System (drug effects)
• Mifepristone (pharmacology)
• Progesterone (administration & dosage, pharmacology)
• Receptors, Progesterone (agonists, antagonists & inhibitors, drug effects, genetics)
• Recombinant Fusion Proteins (drug effects)
• Stress Fibers (ultrastructure)
• Transfection
• Tumor Cells, Cultured (drug effects)