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

Primary transcripts of the human estrogen receptor (ER) and progesterone re ceptor (PR) are subject to a number of alternative splicing events resultin g in a range of variant messenger ribonucleic acid species in receptor-posi tive tissues. Despite in vitro demonstrations of a possible role for some o f 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 s eries of receptor-positive breast tumors. In 35 ER-positive tumors, a commo n 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% cont aining the Delta(5)ER. In 25 of these cases, which were also PR positive, t he 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 varia nts 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 abu ndant 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 Del ta(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 u sed as a discriminator of hormone responsiveness or other clinical end poin ts. Further, the low level of expression of the majority of variant species calls into question their potential for impacting significantly on recepto r function. (J Clin Endocrinol Metab 84: 1370-1377, 1999).