title: Expression and clinical role of antiapoptotic proteins of the bag, heat shock, and Bcl-2 families in effusions, primary tumors, and solid metastases in ovarian carcinoma.
abstract: Cancer progression is associated with reduced apoptosis and increased proliferation. We hypothesized that upregulation of the Bag family of survival cochaperones and its molecular partners of the Bcl-2 and heat shock protein (HSP) families would correlate with disease progression and survival in ovarian cancer. Bag-1, Bag-4, HSP27, HSP70, Bcl-2, and Bcl-X(L) expression was immunohistochemically analyzed in effusions (188) and patient-matched solid tumors (43 primary carcinomas, 81 solid metastases). Results were analyzed for anatomic site-related differences, and association with clinicopathologic parameters and survival. Bag-1, Bag-4, and HSP70 were detected in the tumor cell nuclei and cytoplasm, whereas HSP27, Bcl-2, and Bcl-X(L) had exclusively cytoplasmic localization. Antiapoptotic protein expression in effusions differed significantly from primary tumors and metastases. Cytoplasmic Bag-1 (P=0.002), nuclear and cytoplasmic HSP70 (P<0.001), and Bcl-2 (P=0.001) expression was higher in primary carcinomas and solid metastases compared with effusions, whereas Bcl-X(L) (P=0.01), nuclear Bag-1 (P<0.001), nuclear Bag-4 (P=0.01), and cytoplasmic Bag-4 (P=0.002) were upregulated in effusions. Bcl-X(L) expression was associated with poor response to chemotherapy at diagnosis (P=0.02) and HSP27 expression was associated with high-grade tumors (P=0.01). Increased cytoplasmic HSP70 staining in effusions correlated with poor overall survival for the entire cohort (P=0.01). In primary carcinomas, higher Bcl-2 expression correlated with worse overall (P=0.04) and progression-free (P=0.02) survival. Antiapoptotic proteins are differentially expressed in effusions compared with solid tumors, whereas primary carcinomas and solid metastases have comparable expression patterns. HSP70 expression in effusions may be a prognostic marker of poor survival, with a similar role for Bcl-2 in primary carcinomas.
authors.affiliation: Section for Gynecologic Oncology, Division of Obstetrics and Gynecology, Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Mari Bunkholt
authors.initials: MB
authors.lastname: Elstrand
authors.forename: Lilach
authors.initials: L
authors.lastname: Kleinberg
authors.forename: Elise C
authors.initials: EC
authors.lastname: Kohn
authors.forename: Claes G
authors.initials: CG
authors.lastname: Tropé
authors.forename: Ben
authors.initials: B
authors.lastname: Davidson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000187:drug effects; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001202:Ascitic Fluid / Q000737:chemistry / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000032:analysis; D002277:Carcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000187:drug effects; D005260:Female; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016066:Pleural Effusion, Malignant / Q000737:chemistry / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000187:drug effects; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000096:biosynthesis* / Q000187:drug effects; D051020:bcl-X Protein / Q000096:biosynthesis / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C116906:BAG4 protein, human; C091732:BCL2-associated athanogene 1 protein; C494811:BCL2L1 protein, human; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D051020:bcl-X Protein