The Role of 14-3-3ζ in Tamoxifen Resistance and Breast Cancer Recurrence Open Access

Thistle, Jake Edward (2016)

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Background. Overexpression of 14-3-3ζ has been linked to breast cancer recurrence in several studies, including studies assessing its effect on tamoxifen resistance.

Methods. A case-control study, nested in a population 11,251 females of the Jutland Peninsula aged 35-69 diagnosed with stage I, II, or III breast cancer between 1985 and 2011 registered with the Danish Breast Cancer Cooperative Group, was performed to estimate the effect of 14-3-3ζ expression on tamoxifen resistance. 541 recurrent breast cancer cases with estrogen receptor-positive disease treated with tamoxifen for at least 1 year (ER+/TAM+) and 300 recurrent breast cancer cases in women with estrogen receptor-negative disease never treated with tamoxifen (ER-/TAM-) were identified. 1:1 matching was performed on group membership (ER+/TAM+ or ER-/TAM-), date of surgery, menopausal status, stage, and county. 14-3-3ζ expression was assessed in the nucleus and cytoplasm using tissue microarray immunohistochemistry. The odds ratio (OR) associating 14-3-3ζ expression with breast cancer recurrence was estimated adjusted for confounding using logistic regression.Bias due to expression assay methods was accounted for in an analysis controlling for misclassification and confounding. Inverse-variance weighting Bayesian analysis was performed to further differentiate 14-3-3ζ expression as predictive of tamoxifen resistance or prognostic of breast cancer recurrence.

Results. Patients with above the 50th percentile combined cytoplasmic and nuclear staining showed an association in the ER+/TAM+ group (OR = 1.44, 95% confidence interval = 1.05, 1.99) and a near null association in the ER-/TAM- group (OR = 1.22, 95% confidence interval = 0.82, 1.82). After quantitative bias analysis, associations increased slightly, indicating non-null results are not explained by exposure misclassification, assuming a valid bias model. Evidence was lacking from inverse-variance Bayesian analysis to make conclusions about combined staining as a marker of tamoxifen resistance. Associations for above the 75th percentile of combined staining were moderate in ER+/TAM+ patients (OR = 1.93, 95% confidence interval = 1.15, 3.24) and ER-/TAM- patients (OR = 1.93, 95% confidence interval = 1.03, 3.62), indicating potential prognostic utility.

Conclusion. 14-3-3ζ is a potentially useful prognostic marker of breast cancer recurrence. Further research is needed to determine if 14-3-3ζ has utility beyond established prognostic markers.

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