Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant
Shihua Sun, Cynthia C.T. Sprenger, Robert L. Vessella, Kathleen Haugk, Kathryn Soriano, Elahe A. Mostaghel, Stephanie T. Page, Ilsa M. Coleman, Holly M. Nguyen, Huiying Sun, Peter S. Nelson, Stephen R. Plymate
Shihua Sun, Cynthia C.T. Sprenger, Robert L. Vessella, Kathleen Haugk, Kathryn Soriano, Elahe A. Mostaghel, Stephanie T. Page, Ilsa M. Coleman, Holly M. Nguyen, Huiying Sun, Peter S. Nelson, Stephen R. Plymate
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Research Article Oncology

Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant

Abstract

Progression of prostate cancer following castration is associated with increased androgen receptor (AR) expression and signaling despite AR blockade. Recent studies suggest that these activities are due to the generation of constitutively active AR splice variants, but the mechanisms by which these splice variants could mediate such effects are not fully understood. Here we have identified what we believe to be a novel human AR splice variant in which exons 5, 6, and 7 are deleted (ARv567es) and demonstrated that this variant can contribute to cancer progression in human prostate cancer xenograft models in mice following castration. We determined that, in human prostate cancer cell lines, ARv567es functioned as a constitutively active receptor, increased expression of full-length AR (ARfl), and enhanced the transcriptional activity of AR. In human xenografts, human prostate cancer cells transfected with ARv567es cDNA formed tumors that were resistant to castration. Furthermore, the ratio of ARv567es to ARfl expression within the xenografts positively correlated with resistance to castration. Importantly, we also detected ARv567es frequently in human prostate cancer metastases. In summary, these data indicate that constitutively active AR splice variants can contribute to the development of castration-resistant prostate cancers and may serve as biomarkers for patients who are likely to suffer from early recurrence and are candidates for therapies directly targeting the AR rather than ligand.

Authors

Shihua Sun, Cynthia C.T. Sprenger, Robert L. Vessella, Kathleen Haugk, Kathryn Soriano, Elahe A. Mostaghel, Stephanie T. Page, Ilsa M. Coleman, Holly M. Nguyen, Huiying Sun, Peter S. Nelson, Stephen R. Plymate

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Figure 10

Tumor growth of LNCaP ARv567es cells and xenografts expressing various amounts of ARv567es.

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Tumor growth of LNCaP ARv567es cells and xenografts expressing various a...
(A) 1 × 106 LNCaP pc or LNCaP ARv567es cells were mixed 1:1 with Matrigel and injected s.c. into athymic nude mice (n = 10 per line). When tumors reached a volume of 100–200 mm3, mice were castrated and animals were followed until tumors regrew and reached a volume of 1,000 mm3 or met IACUC criteria for euthanasia. There was no difference in growth rate in intact mice. Following castration, the LNCaP ARv567es tumors, which did not decrease in volume following castration, grew to a significantly larger volume, more quickly than those of controls. *P < 0.01, LNCaP ARv567es tumor volume versus LNCaP pc tumor volume. Values are mean ± SEM. (B–D) The response of tumor volume to castration in 3 different xenografts (intact, n = 12 per xenograft; castrate, n = 12 per xenograft). Note that LuCaP 86.2, which has the majority of its AR in the ARv567es form, had no castration response; LuCaP 136, which has both full-length and variant AR, had a modest response to castration; and LuCaP 35, which has the majority of its AR as ARfl, had a marked decrease in tumor volume in response to castration. Values are mean ± SEM. (E) Western blots of representative xenografts before and 6 weeks after castration using AR sc441, which recognizes ARv567es and ARfl. Lanes were run on different gels.