title: Androgen depletion up-regulates cadherin-11 expression in prostate cancer.
abstract: Men with castration-resistant prostate cancer (PCa) frequently develop metastasis in bone. The reason for this association is unclear. We have previously shown that cadherin-11 (also known as OB-cadherin), a homophilic cell adhesion molecule that mediates osteoblast adhesion, plays a role in the metastasis of PCa to bone. Here, we report that androgen-deprivation therapy up-regulates cadherin-11 expression in PCa. In human PCa specimens, immunohistochemical staining showed that 22/26 (85%) primary PCa tumours from men with castration-resistant PCa expressed cadherin-11. In contrast, only 7/50 (14%) androgen-dependent PCa tumours expressed cadherin-11. In the MDA-PCa-2b xenograft animal model, cadherin-11 was expressed in the recurrent tumours following castration. In the PCa cell lines, there is an inverse correlation between expression of cadherin-11 and androgen receptor (AR), and cadherin-11 is expressed in very low levels or not expressed in AR-positive cell lines, including LNCaP, C4-2B4 and VCaP cells. We showed that AR likely regulates cadherin-11 expression in PCa through an indirect mechanism. Although re-expression of AR in the AR-negative PC3 cells led to the inhibition of cadherin-11 expression, depletion of androgen from the culture medium or down-regulation of AR by RNA interference in the C4-2B4 cells or VCaP cells only produced a modest increase of cadherin-11 expression. Promoter analysis indicated that cadherin-11 promoter does not contain a typical AR-binding element, and AR elicits a modest inhibition of cadherin-11 promoter activity, suggesting that AR does not regulate cadherin-11 expression directly. Together, these results suggest that androgen deprivation up-regulates cadherin-11 expression in prostate cancer, and this may contribute to the metastasis of PCa to bone. Our study suggests that therapeutic strategies that block cadherin-11 expression or function may be considered when applying androgen-ablation therapy.
authors.affiliation: Department of Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Lee
authors.forename: Chien-Jui
authors.initials: CJ
authors.lastname: Cheng
authors.forename: Miao
authors.initials: M
authors.lastname: Huang
authors.forename: Mehmet A
authors.initials: MA
authors.lastname: Bilen
authors.forename: Xiangcang
authors.initials: X
authors.lastname: Ye
authors.forename: Nora M
authors.initials: NM
authors.lastname: Navone
authors.forename: Khoi
authors.initials: K
authors.lastname: Chu
authors.forename: Hsin-Hsin
authors.initials: HH
authors.lastname: Kao
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Yu-Lee
authors.forename: Zhengxin
authors.initials: Z
authors.lastname: Wang
authors.forename: Sue-Hwa
authors.initials: SH
authors.lastname: Lin
mesh_terms: D000728:Androgens / Q000172:deficiency*; D000818:Animals; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000601:surgery; D009919:Orchiectomy; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000728:Androgens; D015820:Cadherins; D009363:Neoplasm Proteins; D011944:Receptors, Androgen; C086960:osteoblast cadherin