BACKGROUND: Several cancer surveys have shown that African-American women (AAW) develop highly aggressive breast tumors and experience about three times higher mortality rates compared with other populations. Generally, breast tumors in AAW are poorly differentiated or undifferentiated and exhibit increased frequency of nuclear atypia, higher mitotic activity, higher S-phase fraction, and tumor necrosis. The molecular factors responsible for these tumor characteristics are mostly unknown. METHODS: To explore whether the aggressive tumor biology observed in AAW is related to distinct alterations in estrogen receptor (ER) isoforms, the relative expression levels of four functionally active ER isoform mRNAs, ERalpha wild type, ERbeta wild type, ERalpha exon 3delta, and ERalpha exon 5delta, were measured by reverse transcriptase-polymerase chain reaction analysis in 18 immunohistochemically ERalpha positive tumors and in 6 ERalpha negative tumors and their matched normal tissues. RESULTS: In the tumors of AAW, the protective ERbeta isoform was decreased significantly compared with matched normal tissues (paired t test; n = 24 patients; P = 0.0018). In addition, both the constitutively active ERalpha exon 5delta and the dominant negative ERalpha exon 3delta mRNA levels were elevated in tumor tissues compared with matched normal tissues (paired t tests; n = 24 patients; P = 0.0002 and P = 0.024, respectively). CONCLUSIONS: The data presented here show for the first time that functionally active ER isoform profiles in the breast tumors of AAW are different from those in Caucasian women. The tumors in AAW are characterized by decreased levels of the protective ERbeta isoform and elevated levels of the constitutively active ERalpha exon 5delta isoform. Variations in estrogen-mediated signaling because of the alterations in these two ER isoforms may account in part for differences in tumor biology between AAW and Caucasian women. Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10274