Purpose: Tamoxifen remains therapy of choice for premenopausal estrogen receptor a^positive breast cancer. However, resistance and recurrence are serious problems. Our previous work indicated that carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) was significantly upregulated in tamoxifen-resistant (TAMr) MCF-7 derivatives.The aim of this study was to determine the functional role of CEACAM6 in endocrine-resistant breast cancer and to retrospectively test whether it was predictive of resistance in a large cohort of breast cancers with long-term follow-up. Experimental Design: siRNA silencing of CEACAM6 was done in TAMr cells and effects on clonogenicity and endocrine sensitivity were determined. CEACAM6 immunohistochemistry was done on a tissue microarray comprising 108 relapsed primary human breast cancers and 243 tamoxifen-sensitive controls. Results: siRNA-mediated silencing of CEACAM6 reduced both clonogenicity and anchoragedependent and anchorage-independent growth of TAMr cells. Importantly, CEACAM6 silencing restored sensitivity of TAMr cells to 4-hydroxytamoxifen and proliferative response to 17h-estradiol. Immunohistochemistry showed significantly more CEACAM expression in the relapsed group compared with nonrelapsed controls [35 of 108 (33.3%) and 32 of 243 (13.2%), respectively; odds ratio, 3.16 (95% confidence interval, 1.83-5.47); P < 0.0001]. Additionally, we derived an outcome predictor model based on CEACAM expression that restratified patients in the Nottingham prognostic index intermediate-risk group into either higher-risk or lower-risk group. Conclusions: Our data support an important role for CEACAM6 in endocrine resistance, which can serve as a powerful predictor of future recurrence.For the last three decades, tamoxifen (TAM) has been the principal endocrine therapy for estrogen receptor a -positive breast cancer patients in both the primary and adjuvant settings and still remains the choice of endocrine therapy in the premenopausal setting (1, 2). However, resistance and recurrence remain a serious problem, with data from clinical studies showing that most patients eventually acquire tamoxifen resistance (3).To elucidate the mechanisms of recurrence following adjuvant endocrine therapy, an expression microarray study by our group showed that carcinoembryonic cell adhesion molecule 6 (CEACAM6) was significantly up-regulated by 20-fold in tamoxifen-resistant (TAMr) MCF-7 derivatives compared with sensitive parental controls (4). CEACAM6 is overexpressed in several human cancers including colorectal adenomas (5) and carcinomas (6), gastric cancers (7), and pancreatic cancers (8, 9). Moreover, CEACAM6 overexpression in colorectal cancer cells has been correlated with reduced overall survival and disease-free survival (6), and CEACAM6 overexpression in colon cancer cells prevented colonocyte differentiation and promoted tumorigenicity in nude mice (10). In pancreatic cancer cells, CEACAM6 overexpression was associated with anoikis resistance and in vivo metastasis (9). CEACA...