Progesterone receptor variants found in breast cells repress transcription by wild-type receptors.

Progesterone, through its nuclear receptors (PR), regulates the development and growth of breast cancers. PR also serve as markers of hormone dependence and prognosis in patients with this disease, and functional PR are required to mediate the antiproliferative effects of progestin therapies. We find that normal and malignant breast cells and tissues can express anomalous forms of PR transcripts. We have isolated four variant PR mRNAs that contain precise deletions of exons encoding sections of the DNA- and hormone-binding domains. The transcripts lack exon 2 (PRdelta2), exon 4 (PRdelta4), exon 6 (PRdelta6), or exons 5 and 6 (PRdelta5,6). On immunoblots, PRdelta4, delta6. and delta5, 6 cloned into the background of the PR A-isoform comigrate with similar proteins present in breast tumor extracts; delta6 and delta5, 6 are dominant-negative transcriptional inhibitors of wild-type A- and B-receptors. We propose that expression of variant PR can compromise the accuracy of receptor measurements as markers of hormone-dependent cancers, and can modify the responses of tumors to progestin therapies.