Coexpression of alternatively spliced estrogen and progesterone receptor transcripts in human breast cancer

Primary transcripts of the human estrogen receptor (ER) and progesterone receptor (PR) are subject to a number of alternative splicing events resulting in a range of variant messenger ribonucleic acid species in receptor-positive tissues. Despite in vitro demonstrations of a possible role for some of these variants in hormonal sensitivity. the clinical significance of this process is uncertain. In this study the coexpression of variant ER and PR transcripts has been documented by RT-PCR and Southern blot analysis in a series of receptor-positive breast tumors. In 35 ER-positive tumors, a common profile of variant ER transcripts was present, with all tumors containing the Delta(2)ER and Delta(7)ER, 94% containing the Delta(4)ER, and 83% containing the Delta(5)ER. In 25 of these cases, which were also PR positive, the most highly expressed PR variants, the Delta(4)PR, Delta(6)PR, and Delta(4/2)PR, a transcript from which a 126-bp portion of PR exon 4 was deleted, were detected in over 90% of the cases. The alternatively spliced ER variants were expressed at higher relative levels than the PR species. which had mean levels of expression less than 10% that of wild-type PR. The most abundant species was the Delta(7)ER, which was present at levels ranging from 29-83% of the wild type. There was no relationship between the level of Delta(7)ER in individual tumors and the pattern of expression of the estrogen-responsive proteins PR and pS2. The common profile of alternatively spliced ER and PR transcripts in breast tumors means that this feature cannot be used as a discriminator of hormone responsiveness or other clinical end points. Further, the low level of expression of the majority of variant species calls into question their potential for impacting significantly on receptor function. (J Clin Endocrinol Metab 84: 1370-1377, 1999).