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BAG-4/SODD and Associated Antiapoptotic Proteins Are Linked to Aggressiveness of Epithelial Ovarian Cancer

Authors' Affiliations: ¹ Medical Oncology Branch, ² Molecular Signaling Section, Laboratory of Pathology, ³ Radiation Oncology Branch, and ⁴ Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and ⁵ Pathology Clinic, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway

Requests for reprints: Christina M. Annunziata, Medical Oncology Branch, National Cancer Institute, NIH, Building 10, Room 4N115, 10 Center Drive, Bethesda, MD 20892-1374. Phone: 301-402-7259; Fax: 301-496-9956; E-mail: annunzic{at}mail.nih.gov.

Purpose: We hypothesized that elevated expression in ovarian cancer of the BAG family of prosurvival proteins and associated partners would be associated with clinical features of aggressiveness in ovarian cancer.

Experimental Design: Expression patterns of BAG-1, BAG-3, BAG-4, and Bcl-xL were determined by immunohistochemical analysis of tissue samples obtained at diagnosis from 28 women with stage III or stage IV ovarian cancer treated with cisplatin, paclitaxel, and cyclophosphamide after initial cytoreduction. Association of these proteins, BAG-6, heat shock protein 70 (Hsp70), Hsp27, and Bcl-2, with clinical variables was tested in ovarian cancer tissue arrays from Gynecologic Oncology Group tissue bank.

Results: A statistically significant relationship was found between elevated cytoplasmic expression of BAG-4 and improved overall (P = 0.0002) and progression-free survival (P = 0.003) in the prospectively collected samples. Bcl-2 staining was significantly more frequent on the tissue array in lower stage (P = 0.005) and grade (P = 0.0009) tumors, whereas Hsp70 was prominent in higher grade cases (P = 0.002). Furthermore, Bcl-xL was more closely associated with serous compared with endometrioid ovarian cancers (P = 0.004).

Conclusion: Unexpectedly, cytoplasmic expression of BAG-4 and Bcl-2 marked less aggressive ovarian cancer, whereas nuclear Hsp70 suggested more aggressive behavior. Bcl-xL may play a more prominent function in the pathology of serous histology ovarian cancers compared with the endometrioid subtype. The findings presented here support involvement of these proteins in the propagation of ovarian cancer and provide a basis for the development of molecular therapeutics modulating these survival pathways.