Chemotherapy resistance is a significant contributor to treatment failure and death in men with
hormone-refractory
prostate cancer. One unexplored mechanism for drug resistance is the induction of stress response
proteins referred to as the
glucose-regulated proteins (GRPs). We sought to determine the level of expression of
GRP78, the best characterized GRP in lymph node-positive
prostate cancer. Archived,
paraffin-embedded, radical
prostatectomy specimens were obtained from 153 patients with lymph node-positive
prostate cancer (stage D1). The level of
GRP78 expression was determined by immunohistochemistry. We assessed the expression and specificity of
GRP78 immunoreactivity in benign prostatic tissue,
prostate cancer, and
lymph node metastasis. We correlated the intensity of immunopositivity with
prostate cancer recurrence and survival. Whereas immunohistochemical staining demonstrated that all prostate tissue was immunoreactive for
GRP78, the intensity of expression was markedly higher in the primary
tumor compared with areas of benign epithelium.
GRP78 expression was also evident in
lymph node metastases although less intensely than in the primary
tumor. Patients with strong
GRP78 immunoreactivity in the primary
tumor are at higher risk for clinical recurrence (relative risk = 2.0, P = .019) and death (relative risk = 1.8, P = .024) than patients with weak
GRP78 expression. This finding confirms that
GRP78 protein expression is significantly higher in
prostate cancer than in benign prostatic tissue. The intensity of expression is significantly associated with survival and clinical recurrence.
GRP78 has considerable potential not only as a prognostic
indicator but also as a potential therapeutic target.