Abstract 3134: CCN3 is a prognostic biomarker and functional mediator of prostate cancer bone metastasis

Abstract

Abstract Background: Prostate cancer commonly metastasizes to the bone, resulting in pathological fractures and poor prognosis. CCN3/NOV (Nephroblastoma overexpressed) is a secreted protein with a known role in breast cancer metastasis to bone. However, in prostate cancer, CCN3 has been ascribed conflicting roles; some studies suggest that CCN3 promotes prostate cancer metastasis while others argue a tumor suppressor role for CCN3 in this disease. Indeed, in the latter context, CCN3 has been shown to sequester the androgen receptor (AR) and suppress AR signaling. The C-terminal domain of CCN3 is thought to mediate many the protein’s pro-metastatic functions given its role in binding to growth factors and promoting dimerization of CCN family members. We hypothesize that the CCN3 CT domain is required to promote osteolytic PC bone metastasis and that CCN3 represents a prognostic biomarker in primary PC tumors to predict recurrence to bone. Methods: CCN3WT and CCN3ΔCT were overexpressed in LNCaP C4-2 cells. The role of CCN3 was assessed with in vitro proliferation, migration and invasion assays, and in vivo through intracardiac injection in male Nude mice (Nu/Nu). Ex vivo µCT scans were performed on murine bone metastasis specimens. CCN3 expression was assessed in two unique tissue microarrays (TMA) comprising over 1500 human primary prostate tumor using different anti-CCN3 antibodies with immunohistochemistry and immunohistofluorescnece, respectively. Results: While CCN3WT and CCN3ΔCT had little effect in vitro on cell proliferation, migration or invasion, intracardiac injection of CCN3WT resulted in increased incidence of bone metastasis compared to empty vector control and CCN3ΔCT. Ex vivo µCT revealed decreased bone mineral density in bones from mice injected with CCN3WT cells compared to empty vector control and CCN3ΔCT expressing LNCaP C4-2 cells. In both TMAs studied, high CCN3 expression in tumor epithelium correlated with increased risk of biochemical relapse and bone metastasis at 5 years and 15 years post- surgical resection, respectively. Conclusion: CCN3 requires its C-terminal domain for its bone metastatic function, and CCN3 is correlated with aggressive disease biology in primary prostate cancer specimens. These findings point to CCN3 protein expression as a biomarker that can be useful in predicting prostate cancer aggressiveness and recurrence to bone, while providing clarity on CCN3’s functional role as a mediator of prostate cancer bone metastasis. Citation Format: Matthew Dankner, Veronique Ouellet, Laudine Desreumaux-Communal, Estelle Schmitt, Dru Perkins, Matthew G. Annis, Veronique Barres, Christine Caron, Anne-Marie Mes-Masson, Fred Saad, Peter M. Siegel. CCN3 is a prognostic biomarker and functional mediator of prostate cancer bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3134.