Abstract P6-08-27: Glucose-regulated protein 78 and C/-EBP homologous protein predict disease-free survival and responsiveness to chemotherapy in breast cancer
Authors: Yi-Zi Zheng, Zhi-Gang Cao, Xin Hu, Zhi-Ming Shao
Journal: Cancer Research (2015)

Abstract Background Cancer cells are generally under endoplasmic reticulum(ER) stress. Notably, the ability of cells to respond to ER stress is critical for cell survival, and chronic or unresolved ER stress can lead to apoptosis. Glucose-regulated protein (GRP) 78 and C/-EBP homologous protein (CHOP) are commonly used as markers of endoplasmic reticulum (ER) stress. As an ER chaperone, GRP78 functions as a potent anti-apoptotic factor and confers drug resistance, whereas CHOP is a key initiating factor of ER stress-related cell death. The clinical implications of GRP78 and CHOP, however, have not been fully studied in breast cancer. In this study, we aimed to investigate the predictive value of GRP78 and CHOP in breast cancer patients who underwent adjuvant chemotherapy. Methods: An immunohistochemistry screen for GRP78 and CHOP was performed using a tissue microarray (TMA) containing 250 tumors from female patients diagnosed with invasive ductal breast carcinoma at the Fudan University Shanghai Cancer Center. The staining results were scored semi-quantitatively, and a prediction model was constructed to verify the hypothesis. Results: In this retrospective study cohort, positive GRP78 staining was detected in 52.6% (n = 112; 52.6% positive, 47.4% negative) of tumors, and CHOP staining was present in 56.3% (n = 120; 56.3% positive, 43.7% negative) of cases. In Kaplan-Meier analysis, CHOP correlated with prolonged disease-free survival (DFS; P = 0.001), whereas GRP78 showed an opposite association (P &amp;lt; 0.001). Moreover, in a GRP78-positive subset, CHOP overexpression correlated with a lower risk of recurrence. A further multivariate COX analysis revealed that positive GRP78 staining cases exhibited a higher likelihood for disease events (HR = 4.573; 95% CI: 2.291-9.128; P &amp;lt; 0.001), while CHOP positivity was indicative of lower risk for recurrence (HR = 0.385, 95% CI: 0.215-0.688; P = 0.001). In the receiver operating characteristic (ROC) analysis, the prediction capability of the predictive model combining the above two markers surpassed that of a traditional model (P = 0.0085 for the area under the curve comparison). Within the anthracycline-treatment subgroup, the combined GRP78 and CHOP exhibited similar predictive significance. Conclusions: Collectively, our findings suggest a tight association between ER stress markers and clinical outcomes for female patients diagnosed with invasive ductal breast carcinoma. Adding these two ER stress markers to traditional prognostic factors provides a more sensitive and accurate predictive model for female patients with invasive ductal breast cancer. Moreover, the combination of GRP78 and CHOP has predictive value for responsiveness to anthracycline-based adjuvant breast cancer chemotherapy. Thus, our findings provide insights into further applications of GRP78 and CHOP, potentially providing additional predictive information for oncologists with regard to choosing treatment regimens. Citation Format: Yi-Zi Zheng, Zhi-Gang Cao, Xin Hu, Zhi-Ming Shao. Glucose-regulated protein 78 and C/-EBP homologous protein predict disease-free survival and responsiveness to chemotherapy in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-27.