BAG-1L (BCL-2-associated athanogene-1L) is a critical co-regulator that binds to and transactivates the androgen receptor (AR), leading to prostate cancer development and progression. Studies investigating the clinical importance of BAG-1L protein expression in advanced prostate cancer have been limited by the paucity of antibodies that specifically recognize the long isoform.
In this study, we have developed and validated a new BAG-1L specific antibody using multiple orthogonal methods across several cell lines with and without genomic manipulation of BAG-1L and all BAG-1 isoforms. Following this, we performed exploratory immunohistochemistry (IHC) to determine BAG-1L protein expression in normal human, matched castration-sensitive prostate cancer (CSPC) and castration-resistant prostate cancer (CRPC), unmatched primary and metastatic CRPC, and early breast cancer tissues. We demonstrated higher BAG-1L protein expression in CRPC metastases than in unmatched, untreated, castration-sensitive prostatectomies from men who remained recurrence-free for 5 years. In contrast, BAG-1L protein expression did not change between matched, same patient, CSPC, and CRPC biopsies, suggesting BAG-1L protein expression may be associated with more aggressive biology and the development of castration resistance. Finally, in a cohort of patients that universally developed CRPC, there was no association between BAG-1L protein expression at diagnosis and time to CRPC or overall survival, and no association between BAG-1L protein expression at CRPC biopsy and clinical outcome from AR targeting therapies or docetaxel chemotherapy. The limitations of this study include the requirement to validate the reproducibility of the assay developed, the potential influence of pre-analytical factors, timing of CRPC biopsies, relatively small patient numbers, and heterogenous therapies, on BAG-1L protein expression, and the clinical outcome analyses performed. We describe a new BAG-1L specific antibody that the research community can further develop to elucidate the biological and clinical significance of BAG-1L protein expression in malignant and non-malignant disease.
Laboratory investigation; a journal of technical methods and pathology. 2023 Aug 29 [Epub ahead of print]
Antje Neeb, Ines Figueiredo, Bora Gurel, Daniel Nava Rodrigues, Jan Rekowski, Ruth Riisnaes, Ana Ferreira, Susana Miranda, Mateus Crespo, Daniel Westaby, Maria de Los Dolores Fenor de La Maza, Christina Guo, Juliet Carmichael, Rafael Grochot, Nina Tunariu, Andrew C B Cato, Stephen R Plymate, Johann S de Bono, Adam Sharp
Institute of Cancer Research, London, UK., Institute of Cancer Research, London, UK; Royal Marsden NHS Foundation Trust, London, UK., Royal Marsden NHS Foundation Trust, London, UK., Karlsruhe Institute of Technology (KIT), Institute for Biological and Chemical Systems-Biological Information Processing (IBCS-BIP)., University of Washington, Seattle, Washington, USA; Geriatrics Research, Education and Clinical Center, VAPSHCS, Seattle, Washington., Institute of Cancer Research, London, UK; Royal Marsden NHS Foundation Trust, London, UK. Electronic address: ., Institute of Cancer Research, London, UK; Royal Marsden NHS Foundation Trust, London, UK. Electronic address: .