GRP78 as a novel predictor of responsiveness to chemotherapy in breast cancer.
The discovery of predictive factors for chemoresistance is critical for improving adjuvant therapy for cancer patients. The 78-kDa glucose-regulated protein (GRP78), widely used as an indicator of the unfolded protein response (UPR), is induced in the tumor microenvironment. In vitro studies suggest that GRP78 confers chemoresistance to topoisomerase inhibitors, such as Adriamycin (doxorubicin). Here, we report on a retrospective cohort study of 127 stage II and III breast cancer patients who were treated with Adriamycin-based chemotherapy. Archival tumor specimens were available for analysis and the relationship of GRP78 expression level to "time to recurrence" (TTR), used as a surrogate marker for drug resistance, was examined. Our data show that 67% of the study subjects expressed high level of GRP78 in their tumors before the initiation of chemotherapy and suggest an association between GRP78 positivity and shorter TTR [hazard ratio (HR), 1.78; P = 0.16]. Interestingly, subgroup analysis reveals that the HR for the GRP78-positive group increased significantly among patients who did not receive further taxane treatment (HR, 3.00; P = 0.022) and among mastectomy patients (HR, 3.33; P = 0.027). The HR was even stronger among mastectomy patients who did not receive further taxane treatment (HR, 4.82; P = 0.010). The use of GRP78 as a predictor for chemoresponsiveness and the potential interaction of GRP78 and/or the UPR pathways with taxanes warrant larger studies.
Lee
Eunjung
E
Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA 90089-9176, USA.
Nichols
Peter
P
Spicer
Darcy
D
Groshen
Susan
S
Yu
Mimi C
MC
Lee
Amy S
AS
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001324:Autoantigens / Q000032:analysis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D006360:Heat-Shock Proteins / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D018832:Molecular Chaperones / Q000032:analysis*; D009367:Neoplasm Staging; D017698:Postmenopause; D011237:Predictive Value of Tests; D017697:Premenopause; D011379:Prognosis; D012008:Recurrence; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001324:Autoantigens; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones