Low expression of the androgen-induced tumor suppressor gene PLZF and lethal prostate cancer

Abstract

Background: 4%–9% of prostate cancers harbor homozygous deletions of the androgen-induced tumor suppressor gene, promyelocytic leukemia zinc finger (PLZF, ZBTB16). PLZF loss induces an in vitro phenotype of castration resistance and enzalutamide resistance. The association of low expression of PLZF and clinical outcomes is unclear. Methods: We assessed PLZF mRNA expression in patients diagnosed with primary prostate cancer during prospective follow-up of the Health Professionals Follow-up Study (HPFS; n ¼ 254) and the Physicians' Health Study (PHS; n ¼ 150), as well as in The Cancer Genome Atlas (n ¼ 333). We measured PTEN status (using copy numbers and IHC) and transcriptional activation of the MAPK pathway. Patients from HPFS and PHS were followed for metastases and prostate cancer–specific mortality (median, 15.3 years; 113 lethal events). Results: PLZF mRNA expression was lower in tumors with PLZF deletions. There was a strong, positive association between intratumoral androgen receptor (AR) signaling and PLZF expression. PLZF expression was also lower in tumors with PTEN loss. Low PLZF expression was associated with higher MAPK signaling. Patients in the lowest quartile of PLZF expression compared with those in the highest quartile were more likely to develop lethal prostate cancer, independent of clinicopathologic features, Gleason score, and AR signaling (odds ratio, 3.17; 95% confidence interval, 1.32–7.60). Conclusions: Low expression of the tumor suppressor gene PLZF is associated with a worse prognosis in primary prostate cancer. Impact: Suppression of PLZF as a consequence of androgen deprivation may be undesirable. PLZF should be tested as a predictive marker for resistance to androgen deprivation therapy.