ER-α36, a Novel Variant of ER-α, is Expressed in ER-positive and -negative Human Breast Carcinomas

Background The status of estrogen receptor-alpha (ER-alpha) expression is one of the most important diagnostic and prognostic factors of breast cancer. ER-alpha is a 66-kDa, ligand-induced transcription factor, characteristically detected in the cell nucleus by immunohistochemistry (IHC) in breast cancer specimens. Recently, we identified and cloned a 36-kDa novel variant of ER-alpha, ER-alpha36, which lacks both transactivation domains and functions as a dominant-negative effector of transactivation activities of the full-length ER-alpha (ER-alpha66) and ER-beta. ER-alpha36 primarily localizes to the cytoplasm and plasma membrane, and responds to both estrogens and antiestrogens by transducing membrane-initiated signaling cascades, stimulating proliferation and possibly contributing to a more aggressive phenotype in breast carcinomas. ER-alpha36 is expressed in established ER-positive and -negative breast cancer cell lines. However, its expression and localization in breast cancer specimens have not been evaluated. As ER-alpha36 may play important roles in breast cancer tumorigenesis, it is of clinical importance to examine the expression pattern of ER-alpha36, in addition to that of ER-alpha66, for more comprehensive molecular profiling of breast carcinomas. Patients and methods Thirty-one breast cancer patient tissues were evaluated for ER-alpha36 and ER-alpha66 protein expression status by IHC and six additional patient tissue samples were analyzed by Western blot analysis using antibodies specific to ER-alpha66 or ER-alpha36. Results Our experiments reveal a cytoplasmic and plasma-membrane-associated expression pattern of ER-alpha36 in both ER-alpha66-positive and -negative breast cancer samples. Furthermore, ER-alpha36 expression appears to be associated with decreasing nuclear and/or cytoplasmic ER-alpha66 expression, suggesting its potential use as a diagnostic and prognostic marker. Conclusion ER-alpha36 is a novel isoform of ER-alpha, frequently expressed in ER-alpha66-negative cancers, whose detection may provide additional information for better diagnosis and prognosis.