A ROLE FOR ESTROGEN-RECEPTOR VARIANTS IN ENDOCRINE RESISTANCE

We have isolated an estrogen-receptor (ER)-variant mRNA from ER-negative/progesterone receptor (PgR)-positive human breast cancers. This variant lacks exon 5 of the hormone-binding domain, resulting in a truncated receptor protein which is unable to bind estrogen. In vitro experiments show that the exon 5 variant possesses constitutive ER activity. For example, when transfected into ER-negative MDA-MB-231 breast cancer cells, it stimulates an estrogen-responsive element (ERE)-dependent reporter system in the presence or absence of exogenous hormone. Proliferation is unaffected by the antiestrogen tamoxifen, which usually inhibits the growth of MCF-7 cells, suggesting that the exon 5 variant may be important clinically in drug resistance. Preliminary studies have found expression of the exon 5 variant transcript in ER-positive breast cancers, but these studies need to be expanded to detect the protein in tumors. It is also possible that ER variants which influence cell proliferation may be involved in carcinogenesis. In this context, we have identified a novel ER variant in a preliminary survey of hyperplastic lesions which are thought to be precursors of invasive breast cancer. This variant possesses a single base-pair alteration in the hormone-binding domain, and exhibits enhanced stimulation of an ERE-reporter system when cotransfected into MDA-MB-231 breast cancer cells. We are currently evaluating its prevalence in premalignant breast lesions, and its ability to influence cell proliferation.