About 75% of breast tumors are positive for the estrogen receptor (ER) or progesterone receptor (PgR) or both, and estrogen is the main stimulant in the development and growth of these tumors. Tamoxifen, an estrogen receptor antagonist has been endocrine treatment for hormone-sensitive breast cancer for more than 20 years. However, the underlying cause of treatment failure in many breast cancer patients receiving tannoxifen is resistance to tamoxifen. The mechanisms of tamoxifen and the molecular events responsible for resistance to tamoxifen are not fully understood. Two ER subtypes, ERalpha and ERbeta, activate the Activator Protein-1 (AP-1) response elements, and through interactions between ERs and the AP-1 transcription factors c-fos and c-jun, these transcription factors regulate the genes involved in many cellular processes, including proliferation, differentiation, cell motility, and apoptosis. Thus, the interaction between ERs and AP-1 could be important clinically and could have bearing on the response to tamoxifen. Tamoxifen acts as an agonist on genes under the control of an AP-1 response elements when ERalpha or ERbeta is expressed. AP-1 blockade supresses mitogenic signals from multiple different peptide growth factors as welt as estrogen, and inhibits the growth of MCF-7 breast cancer cells both in vitro and in vivo. Tamoxifen actually activate the AP-1 transcription factor. Increased AP-1 activity in breast cancer cells can lead to tannoxifen resistance. The proto-oncogene B-cell lymphoma gene 6 (BCL-6) has been characterized as a, regulator of B-lymphocyte growth and development. BCL-6 is also expressed in the mammary epithelium in nonpregnant animals and during early pregnancy and is expressed in 68% of histologically high-grade ductal breast carcinomas, which are clinically the most aggressive. BCL-6 is a potent repressor of transcriptional activity mediated by AP-1 factors. We hypothesize that increased BCL-6 in breast cancer cells might block tamoxifen resistance by repressing AP-1, eventually resulting in apoptosis. We also suggest that BCL-6 expression must be analyzed in ER-positive breast cancer patients and the results must be correlated with predictive and prognostic factors and survival. (C) 2004 Elsevier Ltd. All rights reserved.