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17β-Estradiol upregulates and activates WOX1/WWOXv1 and WOX2/WWOXv2 in vitro: potential role in cancerous progression of breast and prostate to a premetastatic state in vivo

Oncogene volume 24, pages 714–723 (2005)Cite this article

Abstract

Human WWOX gene encodes a proapoptotic WW domain-containing oxidoreductase WOX1 (also named WWOX, FOR2 or WWOXv1). Apoptotic and stress stimuli activate WOX1 via Tyr33 phosphorylation and nuclear translocation. WOX1 possesses a tetrad NSYK motif in the C-terminal short-chain alcohol dehydrogenase/reductase (SDR) domain, which may bind estrogen and androgen. Here, we determined that 17β-estradiol (E2) activated WOX1, p53 and ERK in COS7 fibroblasts, primary lung epithelial cells, and androgen receptor (AR)-negative prostate DU145 cells, but not in estrogen receptor (ER)-positive breast MCF7 cells. Androgen also activated WOX1 in the AR-negative DU145 cells. These observations suggest that sex hormone-mediated Tyr33 phosphorylation and nuclear translocation of WOX1 is independent of ER and AR. Stress stimuli increase physical binding of p53 with WOX1 in vivo. We determined here that E2 increased the formation of p53/WOX1 complex and their nuclear translocation in COS7 cells; however, nuclear translocation of this complex could not occur in MCF7 cells. By immunohistochemistry, we determined that progression of prostate from normal to hyperplasia, cancerous and metastatic stages positively correlate with upregulation and activation of WOX1 and WOX2 (FOR1/WWOXv2). In contrast, breast cancer development to a premetastatic state is associated with upregulation and Tyr33 phosphorylation of cytosolic WOX1 and WOX2, followed by significant downregulation or absent expression during metastasis. These Tyr33-phosphorylated proteins are mostly located in the mitochondria without translocating to the nuclei, which is comparable to those findings in cultured breast cancer cells. Together, sex steroid hormone-induced activation of WOX1 and WOX2 is independent of ER and AR, and this activation positively correlates with cancerous progression of prostate and breast to a premetastatic state.

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Acknowledgements

Research was supported by the Department of Defense (DAMD17-03-1-0736) to NSC. We thank Ms Terri Zimmer for antibody production in rabbits, and Dr Robert I Richards of the University of Adelaide, Australia, in contributing to the production of antibodies against WOX1/FOR2 and WOX2/FOR1. LJH is currently a visiting scientist from the National Cheng Kung University Medical College, Taiwan, and supported by the Ministry of Education, Taiwan, Republic of China (Grant 91-B-FA09-1-4). JL was a Guthrie Scholar from the Wilkes University, Wilkes-Barre, PA.

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Authors and Affiliations

  1. Guthrie Research Institute, Laboratory of Molecular Immunology, 1 Guthrie Square, Sayre, PA, 18840, USA

    Nan-Shan Chang, Lori Schultz, Li-Jin Hsu & Jennifer Lewis

  2. Department of Pathology, University of Colorado Health Sciences Center, Denver, CO, 80262, USA

    Meng Su & Chun-I Sze

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  1. Nan-Shan Chang
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Correspondence to Nan-Shan Chang.

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Chang, NS., Schultz, L., Hsu, LJ. et al. 17β-Estradiol upregulates and activates WOX1/WWOXv1 and WOX2/WWOXv2 in vitro: potential role in cancerous progression of breast and prostate to a premetastatic state in vivo. Oncogene 24, 714–723 (2005). https://doi.org/10.1038/sj.onc.1208124

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