Epithelial-mesenchymal transition (EMT) is a biological process where cells lose their epithelial characteristics and acquire a mesenchymal phenotype with increased migratory behavior. EMT could lead to increase in motility, invasivenes- sand metastatic capabilities of cancer cells (4,5). Recently, 

Hormone therapy targeting estrogen receptor α (ERα) is the most effective treatment for breast cancer. However, this treatment eventually fails as the tumor develops resistance. Although reduced expression of ER-α is a known contributing factor to endocrine resistance, the mechanism of ER-α downregulation in endocrine resistance is still not fully understood. The present study shows that Slug has an inverse relationship with ERα in breast and prostate cancer patient samples. Also the inhibition of Slug blocks mammary stem cell activity in primary mammary epithelial cells. We hypothesize that Slug may be a key transcription factor in the regulation of ERα expression. To understand the Slug-ERα signaling pathway, we employed resistant cell line MCF-TAMR (ERα relatively negative) derived from its parental MCF-7 (ERα positive) cell line and assessed changes in cell phenotype, activity and response to therapy. Conversely, we performed knockdown of Slug in the highSlug expressing cell line MDA-MB-231 and assessed reversal of the mesenchymal phenotype. Microarray analysis showed that Slug is overexpressed in high grade breast and prostate cancer tissues. Additionally, Slug overexpression leads to drug resistance. Furthermore, we demonstrated that Slug binds directly to ERα promoter E-boxes and represses ERα expression. This resulted in decrease in epithelial-to-mesenchymal transition in cancer cells. These findings demonstrate that Slug, by regulation of ERα expression, contributes to tumor progression and could serve as an important target for cancer therapy. Introduction Mechanisms of drug resistance include many factors, including decreased intracellular drug concentration which could result from increased drug efflux via the ATP binding cassette (ABC) transporters such as MDR-1/P-glycoprotein. In addition, decreased conversion of the drug to an active form, and altered amount of drug target or altered target type (1,2) could influence resistance. ER-α is a hormone-dependent nuclear transcription factor that is expressed in ~70% of breast tumors. Tamoxifen treatment decreases cancer recurrence by 50% and reduces the annual breast cancer death rate by 25-30% (3). However, many patients with ERα positive breast cancer eventually acquire resistance to tamoxifen (3). Epithelial-mesenchymal transition (EMT) is a biological process where cells lose their epithelial characteristics and acquire a mesenchymal phenotype with increased migratory behavior. EMT could lead to increase in motility, invasivenessand metastatic capabilities of cancer cells (4,5). Recently, mesenchymal-like characteristics have been associated with resistance to erlotinib, gefitinib, and cetuximab treatment in non-small cell lung cancer, head and neck squamous cell carcinoma, pancreatic cancer and hepatocellular carcinoma (6-9). Tumors arise in tissues and organs that undergo constant remodeling and regeneration. We hypothesized that tumor initiation and progression are steps driven by cancer stem cells (CSCs). Cancer stem cells have been isolated and characterized initially from leukemia and subsequently from solid tumors, including brain, breast, prostate, colon and liver cancer (10-14). In the cancer-stem-cell model of drug resistance, tumors may express a population of drug-resistant pluripotent cells that can survive chemotherapy and subsequently regrow into metastatic tumors (15,16). Slug (Snail2), a C2H2-type zinc finger transcription factor, also an EMT marker, has been identified in aggressive cancers and is correlated with worse clinical outcomes in colon and ovarian cancers (17,18). Slug and Sox9 cooperatively determine the mammary stem cell state (6) and Slug is highly expressed in triple-negative breast cancer (19). However, the role of Slug in the development breast cancer drug resistance is unclear. Slug contributes to cancer progression by direct regulation of ERα signaling pathway YOUqIANG LI1,2, YANYUAN WU1,2, THOMAS C. ABBATIELLO1, WARREN L. WU1, JU RI KIM1, MARIANNA SARKISSYAN1, SUREN SARKISSYAN1, SEYUNG S. CHUNG1, YAHYA ELSHIMALI1 and JAYDUTT V. VADGAMA1,2 1Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059; 2University of California at Los Angeles David Geffen School of Medicine, and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA 90024, USA Received October 4, 2014; Accepted November 24, 2014 DOI: 10.3892/ijo.2015. 2878 Correspondence to: Dr Jay V. Vadgama, Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, UCLA School of Medicine, 1731 East 120th Street, Los Angeles,