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


METHODS
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.
Maraqa
Loaie
L
Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.
Cummings
Michele
M
Peter
Mark B
MB
Shaaban
Abeer M
AM
Horgan
Kieran
K
Hanby
Andrew M
AM
Speirs
Valerie
V
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use*; D001940:Breast; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D058851:GPI-Linked Proteins; D006801:Humans; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D034622:RNA Interference; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D046888:Tissue Array Analysis
D015703:Antigens, CD; D018931:Antineoplastic Agents, Hormonal; C504117:CEACAM6 protein, human; D015815:Cell Adhesion Molecules; D004965:Estrogen Antagonists; D058851:GPI-Linked Proteins; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol