PURPOSE: 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.
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 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.
CONCLUSIONS: Our data support an important role for CEACAM6 in endocrine resistance, which can serve as a powerful predictor of future recurrence.
- Antigens, CD
- Antineoplastic Agents, Hormonal
- Breast Neoplasms
- Cell Adhesion Molecules
- Cell Line, Tumor
- Cell Proliferation
- Chemotherapy, Adjuvant
- Drug Resistance, Neoplasm
- Estrogen Antagonists
- GPI-Linked Proteins
- Neoplasm Recurrence, Local
- RNA Interference
- Selective Estrogen Receptor Modulators
- Tissue Array Analysis
- Journal Article
- Research Support, Non-U.S. Gov't