The antiprogestin Lonaprisan inhibits breast cancer cell proliferation by inducing p21 expression.
The ovarian steroid hormone progesterone is essential for normal mammary gland physiology but may also play a role in breast cancer. Highly potent and selective antiprogestins may therefore represent a new treatment option for this disease. Here we studied the effects of the new antiprogestin Lonaprisan on the T47D breast cancer cell line. Strong inhibition of cell proliferation and arrest in the G0/G1 phase were observed, as well as induction of a senescence-like phenotype. This was accompanied by p21 induction through direct binding of Lonaprisan-bound progesterone receptor (PR) to the promoter. Reduction of p21 levels blunted the antiproliferative effects of Lonaprisan. Mutation analysis showed that intact PR DNA-binding properties were needed for p21 induction. Phosphorylation of PR Ser345 was stimulated by Lonaprisan, but this post-translational modification was not required for p21 promoter activation, nor was the interaction with c-Src needed. These results support the rationale for using antiprogestins in breast cancer treatment and warrant further studies to better understand their mode of action.
Bayer Schering Pharma AG, TRG Oncology, Berlin, Germany.
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L
Busia
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H
Faus
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J
Hoffmann
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B
Haendler
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D016922:Cellular Senescence / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D004963:Estrenes / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008024:Ligands; D009154:Mutation; D010766:Phosphorylation; D011374:Progesterone / Q000037:antagonists & inhibitors; D011372:Progestins / Q000037:antagonists & inhibitors*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D005466:Fluorocarbons
D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004963:Estrenes; D008024:Ligands; D011374:Progesterone; D011372:Progestins; D011980:Receptors, Progesterone; D016329:Sp1 Transcription Factor; C493956:CDKN1A protein, human; C419162:lonaprisan; D005466:Fluorocarbons