Increased Expression of Gankyrin and Stemness Factor Oct-4 are Associated with Unfavorable Clinical Outcomes and Poor Benefit of Tamoxifen in Breast Carcinoma Patients

Tamoxifen is the most important treatment component in estrogen receptor positive (ER+) breast carcinoma patients. Tamoxifen resistance incidence presents an important obstacle in clinical treatment. Mechanisms underlying tamoxifen refractory are not completely understood. Although elevated expression of Gankyrin (P28GANK) and stem cell markers Nanog, Oct-4 and Sox-2 have been reported in breast carcinoma, their role in tamoxifen resistance progression has not been explored. In the present study, P28GANK and stem cell markers Nanog, Oct-4 and Sox-2 expression were evaluated using quantitative RT-PCR and immunohistochemical technology in 72 breast carcinoma patients who received tamoxifen as adjuvant anti-hormone treatment. Expression data were correlated with the clinical outcome and survival of patients. Data analysis showed that P28GANK, Oct-4 and Sox-2 transcripts were significantly overexpressed in tamoxifen resistance patients. Immunohistochemical staining indicated that protein expression of P28GANK and Oct-4 were also significantly higher in tamoxifen resistance patients. We have shown a positive correlation between mRNA and protein expression of P28GANK, Oct-4 and Sox-2. Multivariate logistic regression analysis indicated that P28GANK (P = 0.002) and Oct-4 (P = 0.013) overexpression could be negative independent factors of disease outcome. Additionally, in the whole study group, multivariate Cox regression analysis revealed that high expression of P28GANK and Oct-4 remained significant and unfavorable predictive factors for patients’ survival. These findings suggest that Gankyrin and Oct-4 overexpression could promote tamoxifen refractory in breast cancer patients. More studies are warranted to clarify the predictive role of these potential biomarkers for patients who don’t benefit from tamoxifen treatment and their possible application as prognostic markers in ER tamoxifen-treated breast carcinoma patients.