Dysregulation of the PRUNE2/PCA3 genetic axis in human prostate cancer: from experimental discovery to validation in two independent patient cohorts.

Background: We have previously shown that the long non-coding (lnc)RNA prostate cancer associated 3 (PCA3; formerly prostate cancer antigen 3) functions as a trans-dominant negative oncogene by targeting the previously unrecognized prostate cancer suppressor gene PRUNE2 (a homolog of the Drosophila prune gene), thereby forming a functional unit within a unique allelic locus in human cells. Here, we investigated the PCA3/PRUNE2 regulatory axis from early (tumorigenic) to late (biochemical recurrence) genetic events during human prostate cancer progression. Methods: The reciprocal PCA3 and PRUNE2 gene expression relationship in paired prostate cancer and adjacent normal prostate was analyzed in two independent retrospective cohorts of clinically annotated cases post-radical prostatectomy: a single-institutional discovery cohort (n=107) and a multi-institutional validation cohort (n=497). We compared the tumor gene expression of PCA3 and PRUNE2 to their corresponding expression in the normal prostate. We also serially examined clinical/pathological variables including time to disease recurrence. Results: We consistently observed increased expression of PCA3 and decreased expression of PRUNE2 in prostate cancer compared with the adjacent normal prostate across all tumor grades and stages. However, there was no association between the relative gene expression levels of PCA3 or PRUNE2 and time to disease recurrence, independent of tumor grades and stages. Conclusions: We concluded that upregulation of the lncRNA PCA3 and targeted downregulation of the protein-coding PRUNE2 gene in prostate cancer could be early (rather than late) molecular events in the progression of human prostate tumorigenesis but are not associated with biochemical recurrence. Further studies of PCA3/PRUNE2 dysregulation are warranted. Funding: We received support from the Human Tissue Repository and Tissue Analysis Shared Resource from the Department of Pathology of the University of New Mexico School of Medicine and a pilot award from the University of New Mexico Comprehensive Cancer Center. RP and WA were supported by awards from the Levy-Longenbaugh Donor-Advised Fund and the Prostate Cancer Foundation. EDN reports research fellowship support from the Brazilian National Council for Scientific and Technological Development (CNPq), Brazil, and the Associação Beneficente Alzira Denise Hertzog Silva (ABADHS), Brazil. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of New Mexico Comprehensive Cancer Center (CA118100) and the Rutgers Cancer Institute of New Jersey (CA072720).

Breast cancer survival, survival disparities, and guideline-based treatment.

PURPOSE: The role of appropriate therapy in breast cancer survival and survival disparities by race/ethnicity has not been fully elucidated. We investigated whether lack of guideline-recommended therapy contributed to survival differences overall and among Hispanics relative to non-Hispanic white (NHW) women in a case-cohort study. METHODS: The study included a 15% random sample of female invasive breast cancer patients diagnosed from 1997 to 2009 in 6 New Mexico counties and all deaths due to breast cancer-related causes. Information was obtained from comprehensive medical chart reviews. National Comprehensive Cancer Network (NCCN®) guideline-recommended treatment was assessed among white women aged < 70 who were free of contraindications for recommended therapy, had stage I-III tumors, and survived ≥ 12 months. Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer death were estimated using Cox proportional hazards models. RESULTS: Included women represented 4635 patients and 449 breast cancer deaths. Women who did not receive radiotherapy (HR 2.3; 95% CI 1.2-4.4) or endocrine therapy (HR 2.0; 95% CI 1.0-4.0) as recommended by guidelines had an increased risk of breast cancer death, relative to those treated appropriately. Receipt of guideline-recommended therapy did not differ between Hispanic and NHW women for chemotherapy (84.2% vs. 81.3%, respectively), radiotherapy (89.2% vs. 91.1%), or endocrine therapy (89.2% vs. 85.8%), thus did not influence Hispanic survival disparities. CONCLUSIONS: Lack of guideline-recommended radiotherapy or endocrine therapy contributed to survival as strongly as other established prognostic indicators. Hispanic survival disparities in this population do not appear to be attributable to treatment differences.

Identification of an agonist ligand for estrogen-related receptors ERRbeta/gamma.

In order to develop agonist ligands that are specific for the estrogen-related receptors ERRbeta/gamma, a hydrazone with a 4-hydroxy group at one phenyl ring and a 4-diethylamino moiety at the other phenyl ring was synthesized. We demonstrate that compound 3 (DY131; N'-{(1E)-[4-(diethylamino)phenyl]methylene}-4-hydroxybenzohydrazide) effectively and selectively activates ERRbeta/gamma. DY131 had no effect on the structurally related receptors ERRalpha or the estrogen receptors alpha and beta (ERalpha/beta). This work defines a convenient synthesis for a novel and selective pharmacologic tool that can be used to elucidate the biological activities of ERRbeta/gamma.