Abstract
ErbB3 is a transmembrane growth factor receptor that has been implicated in the pathogenesis of human cancer. After finding that a truncated form of ErbB3 was present and upregulated in metastatic prostate cancer cells in lymph nodes and bone, we explored the pathophysiological functions of this unusual form of ErbB3 in the context of mouse calvaria as well as osteoblasts in vitro and the femur microenvironment in vivo. Here we demonstrate that prostate cancer cells expressed an alternatively spliced transcript that encodes a 45-kDa glycosylated protein (p45-sErbB3). The recombinant p45-sErbB3 purified from conditioned medium stimulated calvarial bone formation and induced osteoblast differentiation. Overexpression of p45-sErbB3 in the osteolytic prostate cancer cell line PC-3 converted its phenotype from bone lysing to bone forming upon injection into the femurs of immunodeficient mice. Further, we detected sErbB3 in plasma samples from patients with castration-resistant prostate cancer with bone metastasis. These observations establish that p45-sErbB3 is a structurally and functionally unique gene product of ErbB3 and suggest that p45-sErbB3 is likely one of the factors involved in the osteoblastic bone metastases of prostate cancer.
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Abbreviations
- Ad:
-
adenovirus
- PMO:
-
primary mouse osteoblast
References
Alimandi M, Romano A, Curia MC, Muraro R, Fedi P, Aaronson SA et al. (1995). Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas. Oncogene 10: 1813–1821.
Berruti A, Dogliotti L, Bitossi R, Fasolis G, Gorzegno G, Bellina M et al. (2000). Incidence of skeletal complications in patients with bone metastatic prostate cancer and hormone refractory disease: predictive role of bone resorption and formation markers evaluated at baseline. J Urol 164: 1248–1253.
Bhargava U, Bar-Lev M, Bellows CG, Aubin JE . (1988). Ultrastructural analysis of bone nodules formed in vitro by isolated fetal rat calvaria cells. Bone 9: 155–163.
Chen N, Ye XC, Chu K, Navone NM, Sage EH, Yu-Lee LY et al. (2007). A secreted isoform of ErbB3 promotes osteonectin expression in bone and enhances the invasiveness of prostate cancer cells. Cancer Res 67: 6544–6548.
Choueiri M, Tu S-M, Yu-Lee LY, Lin SH . (2006). The central role of osteoblasts in the metastasis of prostate cancer. Cancer Metastasis Rev 25: 601–609.
Corey E, Quinn JE, Bladou F, Brown LG, Roudier MP, Brown JM et al. (2002). Establishment and characterization of osseous prostate cancer models: intra-tibial injection of human prostate cancer cells. Prostate 52: 20–33.
Hellyer NJ, Kim MS, Koland JG . (2001). Heregulin-dependent activation of phosphoinositide 3-kinase and Akt via the ErbB2/ErbB3 co-receptor. J Biol Chem 276: 42153–42161.
Kraus MH, Issing W, Miki T, Popescu NC, Aaronson SA . (1989). Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors. Proc Natl Acad Sci USA 86: 9193–9197.
Liang AK, Liu J, Mao SA, Siu VS, Lee YC, Lin SH . (2005). Expression of recombinant MDA-BF-1 with a kinase recognition site and a 7-histidine tag for receptor binding and purification. Protein Expr Purif 44: 58–64.
Lin S-H, Lee Y-C, Choueiri M, Wen S, Mathew P, Ye X et al. (2008). Soluble ErbB3 levels in bone marrow and plasma of men with prostate cancer. Clin Cancer Res (in press).
Logothetis C, Lin S-H . (2005). Osteoblasts in prostate cancer metastasis to bone. Nat Rev Cancer 5: 21–28.
Low SH, Wong SH, Tang BL, Subramaniam VN, Hong W . (1991). Apical cell surface expression of rat dipeptidyl peptidase IV in transfected madin-darby canine kidney cells. J Biol Chem 266: 13391–13396.
Naidu R, Yadav M, Nair S, Kutty MK . (1998). Expression of c-erbB3 protein in primary breast carcinomas. Br J Cancer 78: 1385–1390.
Shah RB, Mehra R, Chinnaiyan AM, Shen R, Ghosh D, Zhou M et al. (2004). Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res 64: 9209–9216.
Soos G, Zukowski K, Jones RF, Haas GP, Wang CY . (1996). Heterotopic growth of human prostate carcinoma in the femurs of nude mice: an osseous metastatic model. Int J Cancer 66: 280–281.
Vakar-Lopez F, Cheng C-J, Kim J, Shi GG, Troncoso P, Tu S-M et al. (2004). Up-regulation of MDA-BF-1, a secreted isoform of ErbB3, in metastatic prostate cancer cells and activated osteoblasts in bone marrow. J Pathol 203: 688–695.
Wu TT, Sikes RA, Cui Q, Thalmann GN, Kao C, Murphy CF et al. (1998). Establishing human prostate cancer cell xenografts in bone: induction of osteoblastic reaction by prostate-specific antigen-producing tumors in athymic and SCID/bg mice using LNCaP and lineage-derived metastatic sublines. Int J Cancer 77: 887–894.
Yang J, Fizazi K, Peleg S, Sikes CR, Raymond AK, Jamal N et al. (2001). Prostate cancer cells induce osteoblast differentiation through a cbfa1-dependent pathway. Cancer Res 61: 5652–5659.
Yi ES, Harclerode D, Gondo M, Stephenson M, Brown RW, Younes M et al. (1997). High c-erbB-3 protein expression is associated with shorter survival in advanced non-small cell lung carcinomas. Mod Pathol 10: 142–148.
Acknowledgements
We thank Karen Earley, Weiping Luo, Matthew Galfione for technical assistance, Dr Jian Kuang for critical reading of the manuscript and Christine Wogan for editing the manuscript. This work was supported by National Institutes of Health grants CA111479, P50-CA90270 and DK53176; the Charlotte Geyer Foundation and the Prostate Cancer Foundation.
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Lin, SH., Cheng, CJ., Lee, YC. et al. A 45-kDa ErbB3 secreted by prostate cancer cells promotes bone formation. Oncogene 27, 5195–5203 (2008). https://doi.org/10.1038/onc.2008.156
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DOI: https://doi.org/10.1038/onc.2008.156
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