The endoplasmic reticulum stress markers GRP78 and CHOP predict disease-free survival and responsiveness to chemotherapy in breast cancer.

Abstract

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. We aimed at investigating the predictive values of GRP78 and CHOP in breast cancer patients who underwent adjuvant chemotherapy. An immunohistochemistry screen for GRP78 and CHOP was performed using a tissue microarray 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. In this retrospective cohort study, CHOP correlated with prolonged disease-free survival (HR=0.385, 95% CI 0.215-0.688; P=0.001), whereas GRP78 showed an opposite association (HR=4.573; 95% CI 2.291-9.128; P<0.001). Moreover, in a GRP78-positive subset, CHOP overexpression correlated with a lower risk of recurrence. In the receiver operating characteristic analysis, the prediction capability of the predictive model combining the above two markers surpassed that of the 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. Cumulatively, our findings suggest a tight association between ER stress markers and clinical outcomes for patients with breast cancer.