Abstract
Tamoxifen remains therapy of choice for premenopausal estrogen receptor alpha-positive breast cancer. However, resistance and recurrence are serious problems. Our previous work indicated that carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) was significantly up-regulated 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. 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. siRNA-mediated silencing of CEACAM6 reduced both clonogenicity and anchorage-dependent and anchorage-independent growth of TAMr cells. Importantly, CEACAM6 silencing restored sensitivity of TAMr cells to 4-hydroxytamoxifen and proliferative response to 17beta-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. Our data support an important role for CEACAM6 in endocrine resistance, which can serve as a powerful predictor of future recurrence.
Highlights
Tamoxifen remains therapy of choice for premenopausal estrogen receptor a ^ positive breast cancer
There have been previous observational reports of carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) expression in breast cancer [11, 12], but relatively little is known about its functional role in this disease
Global microarray analysis of atypical ductal hyperplasia, a preinvasive breast lesion with a high likelihood to progress to invasive breast cancer, showed that CEACAM6 expression was higher in cases that progressed to breast cancer [15]
Summary
Tamoxifen remains therapy of choice for premenopausal estrogen receptor a ^ positive breast cancer. 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. CEACAM6 immunohistochemistry was done on a tissue microarray comprising 108 relapsed primary human breast cancers and 243 tamoxifen-sensitive controls. To elucidate the mechanisms of recurrence following adjuvant endocrine therapy, an expression microarray study by our group showed that carcinoembryonic cell adhesion molecule. 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 clinical breast cancer with long-term follow-up
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