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 (PRΔ2), exon 4 (PRΔ4), exon 6 (PRΔ6), or exons 5 and 6 (PRΔ5,6). On immunoblots, PRΔ4, Δ6, and Δ5,6 cloned into the background of the PR A-isoform comigrate with similar proteins present in breast tumor extracts; Δ6 and Δ5,6 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.
Bibliographical noteFunding Information:
Supported by NIH CA 26869 and DK48238; by the U.S. Army DAMD 17-94-5-4026; by the NFCR and by the Tissue Procurement Core of the University of Colorado Cancer Center. JKR was supported by a Thorkildsen Research Fellowship; and AMW by a Veterans of Foreign Wars Fellowship and a stipend from the ORWH, NCI. The results of this study were presented at the Keystone Symposium on The Steroid/Thyroid/Retinoic Acid Gene Family, March, 1996.
- Dominant negative variants
- Hormone dependence
- Progesterone receptors
- Splice variants