Accurate identification of prognostic markers in primary breast cancer is critical for selecting the most beneficial mode of therapy for the affected patients. The estrogen receptor (ER) is a major prognostic marker, indicating the estrogen-responsive nature of breast tumors and the likelihood of response to hormonal therapy. Estrogen receptor variants may possess outlaw functions, acting in a dominant-positive (transcriptionally active in the absence of estrogen) or dominant-negative (transcriptionally inactive, while inhibiting the function of wild-type ER) manner. Developing a strong correlation between particular ER variants and altered estrogen-responsiveness suggests that over-expression of these ER variants or an altered expression ratio of these variants to the wild-type ER may be an important biologic event leading to the formation of hormone-independent, antiestrogen-resistant breast cancer Using a variety of approaches including RNase protection analysis and RT-PCR followed by cloning and sequencing, variant ER mRNAs with complete deletions of exons 5 and 7, in addition to the wild-type ER transcript, have been identified in the ER-negative BT-20 and ER-positive MCF-7 breast tumor cell lines. We have also been able to identify these two variant ER transcripts in a number of breast tumor cell lines both ER-positive and ER-negative. It appears that the exon 5 deletion variant $(\Delta 5)$ is expressed at higher levels than the exon 7 deletion variant $(\Delta 7)$ in each cell line, and the ratio of expression of variant to wild-type ER transcript differed among the cell lines examined. Immunoprecipitation of ER followed by Western blot analysis revealed a truncated receptor in the BT-20 cell line that is the expected size of the purported $\Delta 5$ variant ER protein and which possesses constitutive transcriptional regulatory activity in a yeast expression system. RNase protection analysis also demonstrated a variation in the levels of expression of $\Delta 5$ variant transcripts among stocks of MCF-7 cell lines obtained from different sources. Perhaps more importantly, a preliminary study has suggested that the expression of the $\Delta 5$ variant is modulated in culture by the presence or absence of estradiol