Incidence of androgen receptor and androgen receptor variant 7 coexpression in prostate cancer

Abstract

Background Prostate cancer (PRCA) is an androgen‐driven disease, where androgens act through the androgen receptor (AR) to induce proliferation and survival of tumor cells. Recently, AR splice variant 7 (ARv7) has been implicated in advanced stages of PRCA and clinical recurrence. With the widespread use of AR‐targeted therapies, there has been a rising interest in the expression of full‐length AR and ARv7 in PRCA progression and how these receptors, both independently and together, contribute to adverse clinicopathologic outcomes. Methods Despite a multitude of studies measuring the expression levels of AR and ARv7 in PRCA progression, the results have been inconsistent and sometimes contradictory due to technical and analytical discrepancies. To circumvent these inconsistencies, we used an automated multiplexed immunostaining platform for full‐length AR and ARv7 in human PRCA samples and objectively quantified expression changes with machine learning‐based software. With this technology, we can assess receptor prevalence both independently, and coexpressed, within specific tissue and cellular compartments. Results Full‐length AR and ARv7 expression increased in epithelial nuclei of metastatic samples compared to benign. Interestingly, a population of cells with undetectable AR persisted through all stages of PRCA progression. Coexpression analyses showed an increase of the double‐positive (AR+/ARv7+) population in metastases compared to benign, and an increase of the double‐negative population in PRCA samples compared to benign. Importantly, analysis of clinicopathologic outcomes associated with AR/ARv7 coexpression showed a significant decrease in the double‐positive population with higher Gleason score (GS), as well as in samples with recurrence in under 5 years. Conversely, the double‐negative population was significantly increased in samples with higher GS and in samples with recurrence in under 5 years. Conclusions Changes in AR and ARv7 coexpression may have prognostic value in PRCA progression and recurrence. A better understanding of the prevalence and clinicopathologic outcomes associated with changes in these receptors' coexpression may provide a foundation for improved diagnosis and therapy for men with PRCA.

Development and prevalence of castration-resistant prostate cancer subtypes

“…The prevalence of an AR low/negative expression pattern has generally been underappreciated, but has been observed in a number of experiments ( Table 2 ). [4] , [5] , [7] , [8] , [72] , [73] , [74] , [75] , [76] , [77] , [78] , [79] , [80] , [81] , [82] , [83] , [84] , [85] , [86] , [87] , [88] , [89] More generally, several studies have observed decreased AR protein expression/intensity in hormone-refractory patient metastases, 90 and in hormone-refractory patients when compared to normal, primary, or hormone-sensitive tissue. [86] , [91] CRPC subtypes that exhibit AR low/negative expression patterns (e.g.…”

“… 78 Though inter-experimental variability makes exact estimations of this heterogeneity difficult, several studies support the AR negative/low subpopulation can total up to 30% of cells within a primary tumor. [7] , [8] , [74] , [91] , [98] Furthermore, AR heterogeneity in human CaP bone metastases can be widespread, reaching up to 80% AR protein negativity in some patient cohorts. 99 In CRPC, heterogeneity of AR expression in 265 patients was observed; of these, 31% had AR positivity in <50% of the tumor, 41.5% had <10% AR positivity, and 1.8% of patients had tumors with <1% AR positivity.…”

“…IHC was performed according to Biocare protocol, as previously described. 7 Briefly, tissues were hydrated using xylenes and ethanol, and primary antibody detecting the C-terminus of AR (Abcam Cat. No.…”

“…Objective quantification was determined using InForm version 1.4 software (Perkin Elmer, Waltham, MA, USA) as previously described. [7] , [8] …”

Resveratrol inhibits proliferation and promotes apoptosis via the androgen receptor splicing variant 7 and PI3K/AKT signaling pathway in LNCaP prostate cancer cells

“…A Previous study have shown that ARV7 mRNA and protein levels are significantly increased in hormone-independent PCa cells and clinical specimens, and are associated with postoperative recurrence, distant metastasis and shortened survival time ( 38 ). It is also hypothesized that the structural features of AR-cleavage variants may activate downstream target genes through androgen-independent pathways to effect proliferation of PCa and eventually develop into androgen-independent PCa ( 39 ).…”