Carcinoembryonic antigen cell adhesion molecule 6 predicts breast cancer recurrence following adjuvant tamoxifen.

Abstract

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.

• Authors: Loaie Maraqa, Michele Cummings, Mark B Peter, Abeer M Shaaban, Kieran Horgan, Andrew M Hanby, Valerie Speirs
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 2 Pg. 405-11 (Jan 15 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18223215 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Antineoplastic Agents, Hormonal
• CEACAM6 protein, human
• Cell Adhesion Molecules
• Estrogen Antagonists
• GPI-Linked Proteins
• Selective Estrogen Receptor Modulators
• Tamoxifen
• afimoxifene
• Estradiol

Topics

• Antigens, CD (genetics, metabolism)
• Antineoplastic Agents, Hormonal (pharmacology, therapeutic use)
• Breast
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Cell Adhesion Molecules (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chemotherapy, Adjuvant
• Drug Resistance, Neoplasm
• Estradiol (pharmacology)
• Estrogen Antagonists (pharmacology)
• GPI-Linked Proteins
• Humans
• Neoplasm Recurrence, Local
• Prognosis
• RNA Interference
• Selective Estrogen Receptor Modulators (pharmacology)
• Tamoxifen (analogs & derivatives, pharmacology, therapeutic use)
• Tissue Array Analysis