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.

Effects of endoplasmic reticulum stress on the autophagy, apoptosis, and chemotherapy resistance of human breast cancer cells by regulating the PI3K/AKT/mTOR signaling pathway

“…According to the previous study, cancer cells are usually under endoplasmic reticulum stress (ERS) and they are in a need of a highly specific ER quality-control system which is also named as the unfolded protein response (UPR) to maintain ER homeostasis. 9 In recent years, it has been found that ERS could directly induce autophagy for protein restoration by synthesizing unfolded, misfolded, and damaged proteins and subsequently inducing UPR-mediated upregulation of binding immunoglobulin protein (BiP), which is the dispensable autophagosome formation. 10 Interestingly, the cells' ability of responding to ERS is essential for their survivals, and chronic or unresolved ERS can result in cell apoptosis.…”

Cytidine Deaminase Axis Modulated by miR-484 Differentially Regulates Cell Proliferation and Chemoresistance in Breast Cancer

“…A total of 193 cancerous and 36 noncancerous mammary cases were included in IHC analyses. IHC variables were scored semiquantitatively according to the approach of a prior study (21). The brief details of TMAs construction, IHC staining, and IHC variable evaluation are described in the Supplementary Methods.…”

Advanced oxidation protein products induce apoptosis in podocytes through induction of endoplasmic reticulum stress

“…The UPR initially functions as an adaptive response, but it might trigger apoptosis under prolonged or severe ER stress. ER stress also upregulates CHOP, and thus this molecule is used as another ER stress marker [40]. To investigate whether AOPPs induced ER stress in podocytes, we examined the expression of GRP78 and CHOP by performing RT-PCR and Western blot assays.…”