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

Loaie Maraqa, Michele Cummings, Mark B Peter, Abeer M Shaaban, Kieran Horgan, Andrew M Hanby, Valerie Speirs

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)405-11
Number of pages7
JournalClinical Cancer Research
Volume14
Issue number2
DOIs
Publication statusPublished - 15 Jan 2008

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Carcinoembryonic Antigen
Cell Adhesion Molecules
Tamoxifen
Breast Neoplasms
Recurrence
Small Interfering RNA
Immunohistochemistry
Estrogen Receptor alpha
Estradiol
Odds Ratio
Confidence Intervals
Growth

Keywords

  • Antigens, CD
  • Antineoplastic Agents, Hormonal
  • Breast
  • Breast Neoplasms
  • Cell Adhesion Molecules
  • Cell Line, Tumor
  • Cell Proliferation
  • Chemotherapy, Adjuvant
  • Drug Resistance, Neoplasm
  • Estradiol
  • Estrogen Antagonists
  • GPI-Linked Proteins
  • Humans
  • Neoplasm Recurrence, Local
  • Prognosis
  • RNA Interference
  • Selective Estrogen Receptor Modulators
  • Tamoxifen
  • Tissue Array Analysis
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Carcinoembryonic antigen cell adhesion molecule 6 predicts breast cancer recurrence following adjuvant tamoxifen. / Maraqa, Loaie; Cummings, Michele; Peter, Mark B; Shaaban, Abeer M; Horgan, Kieran; Hanby, Andrew M; Speirs, Valerie.

In: Clinical Cancer Research, Vol. 14, No. 2, 15.01.2008, p. 405-11.

Research output: Contribution to journalArticle

Maraqa, Loaie ; Cummings, Michele ; Peter, Mark B ; Shaaban, Abeer M ; Horgan, Kieran ; Hanby, Andrew M ; Speirs, Valerie. / Carcinoembryonic antigen cell adhesion molecule 6 predicts breast cancer recurrence following adjuvant tamoxifen. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 2. pp. 405-11.
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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.",
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AU - Maraqa, Loaie

AU - Cummings, Michele

AU - Peter, Mark B

AU - Shaaban, Abeer M

AU - Horgan, Kieran

AU - Hanby, Andrew M

AU - Speirs, Valerie

PY - 2008/1/15

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N2 - 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.

AB - 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.

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KW - Breast Neoplasms

KW - Cell Adhesion Molecules

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Chemotherapy, Adjuvant

KW - Drug Resistance, Neoplasm

KW - Estradiol

KW - Estrogen Antagonists

KW - GPI-Linked Proteins

KW - Humans

KW - Neoplasm Recurrence, Local

KW - Prognosis

KW - RNA Interference

KW - Selective Estrogen Receptor Modulators

KW - Tamoxifen

KW - Tissue Array Analysis

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1158/1078-0432.CCR-07-1363

DO - 10.1158/1078-0432.CCR-07-1363

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SP - 405

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JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 2

ER -