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Benign prostatic hyperplasia (BPH) is a non-neoplastic proliferative disease producing lower urinary tract symptoms related to the resulting enlarged prostate. BPH is pathologically characterized by hyperplastic growth in both epithelial and stromal compartments. Androgen signaling is essential for prostate function and androgen blockade is the second-line medical therapy to relieve symptoms of BPH. Here we examined the prostates of probasin promoter-driven prolactin (Pb-PRL) transgenic mice, a robust model of BPH that spontaneously develops prostate enlargement, to investigate prostate regression in response to surgical castration. Serial ultrasound imaging demonstrated very uniform self-limited growth of Pb-PRL prostate volume that is consistent with the benign, limited cellular proliferation characteristic of BPH and that contrasts with the highly variable, exponential growth of murine prostate cancer models. Castration elicited only a partial reduction in prostate volume, relative to castration-induced regression of the normal prostate gland. The anti-androgen finasteride induced a diminished reduction of Pb-PRL prostate volume versus castration. The limited extent of Pb-PRL mouse prostate volume regression correlated with the initial volume of the stromal compartment, suggesting a differential sensitivity of the epithelial and stromal compartments to androgen withdrawal. Indeed, two-dimensional morphometric analyses revealed a distinctly reduced rate of regression for the stromal compartment in Pb-PRL mice. The myofibroblast component of the Pb-PRL prostate stroma appeared normal, but the stromal compartment contained more fibroblasts and extracellular collagen deposition. Like normal prostate, the rate of regression of the Pb-PRL prostate was partially dependent on TGFß and TNF signaling, but unlike the normal prostate, the extent of castration-induced regression was not affected by TGFß or TNF blockade. Our studies show that androgen deprivation can effectively reduce the overall volume of hyperplastic prostate, but the stromal compartment is relatively resistant, suggesting additional therapies might be required to offer an effective treatment for the clinical manifestations of BPH.

Additional file 1: Supplemental Material 1. Role of NRF2 in non-cancerous disease prevention and aging retardation. Supplemental Table S1. Summary of the datasets collected from publicly available kidney tumor tissues versus normal tissue samples*. Supplemental Table S2. Somatic Mutation Analysis Summary of relevant genes*. Supplemental Table S3. Classification of KIRP/pRCC tumor and normal tissues into Type 1 pRCC and Type 2 pRCC. Supplemental Figure S1. NRF2 expression in Type 1 pRCC and Type 2 pRCC tumor tissues versus in normal renal tissues: Boxplots of the NRF2 expression level across TCGA Type 1 or Type 2 pRCC tumor tissues (red) versus the normal renal tissues (blue) were presented (A). NRF2 expression among different stages of Type 1 pRCC tumor tissues versus the matched normal tissue (B) or versus all normal tissues (C) was box-plotted. NRF2 expression among different stages of Type 2 pRCC tumor tissues versus matched normal tissue was box-plotted (D). NRF2 expression was presented in the log2 (TPM + 1) scale format. Data was presented as the mean ± standard deviation (SD). A t-test was used to evaluate the statistical significance of the NRF2 mRNA expression level in renal normal tissues versus either Type 1 or type 2 pRCC tumor tissues. One-way ANOVA was used to compare NRF2 expression among renal normal tissues versus different stages of Type 1 or Type 2 pRCC tumor tissues. The figure was performed using R version 4.0.3. Supplemental Figure S2. Effects of NRF2 expression on Type 1 pRCC patient survival probability: Kaplan-Meier survival analyses of overall survival (OS) from TCGA-Type 1 (A) or Type 2 (B) pRCC cohorts were presented. Patients were grouped into the high NRF2 expression group versus the low NRF2 expression group based on the median NRF2 mRNA expression level in either Type 1 (A) or Type 2 (B) pRCC tumor tissues. Each p-value for the significance from high versus low NRF2 expression was calculated using the log-rank test. The figures were performed using R version 4.0.3. Supplemental Figure S3. Mdm4/MdmX expression in RCC tumor tissues versus in normal tissues: Boxplots of the Mdm4MdmX expression level across TCGA-RCC subtypes in renal tumor (red) versus the associated normal renal tissues (blue) were presented (A). Mdm4MdmX expression among different stages of chRCC (B), ccRCC (C) and pRCC (D) versus normal renal tissues was box-plotted. Mdm4MdmX expression was presented in the log2 (TPM + 1) scale format. Data was presented as the mean ± SD. A t-test was used to evaluate the statistical significance of the mRNA expression level in renal normal versus tumor tissues. One-way ANOVA was used to compare Mdm4MdmX expression among renal normal tissues versus different stages of RCC tumor tissues. The figure was performed using R version 4.0.3. Supplemental Figure S4. Effects of Mdm4/MdmX expression on RCC patient survival probability: Kaplan-Meier survival analyses of OS from TCGA-RCC cohorts of ccRCC (A), chRCC (B) and pRCC(C) were presented. Patients were grouped into the high Mdm4/MdmX expression group versus the low Mdm4/MdmX expression group based on the median Mdm4/MdmX mRNA expression. Each p-value for the significance from high versus low Mdm4/MdmX expression was calculated using the log-rank test. The figures were performed using R version 4.0.3. Supplemental Figure S5. AKT2 expression in RCC tumor tissues versus in normal tissues: Boxplots of the AKT2 expression level across TCGA-RCC subtypes in renal tumor (red) versus the associated normal renal tissues (blue) were presented (A). AKT2 expression among different stages of chRCC (B), ccRCC (C) and pRCC (D) versus normal renal tissues was box-plotted. AKT2 expression was presented in the log2 (TPM + 1) scale format. Data was presented as the mean ± SD. A t-test was used to evaluate the statistical significance of the mRNA expression level in renal normal versus tumor tissues. One-way ANOVA was used to compare AKT2 expression among renal normal tissues versus different stages of RCC tumor tissues. The figure was performed using R version 4.0.3. Supplemental Figure S6. Effects of AKT2 expression on RCC patient survival probability: Kaplan-Meier survival analyses of OS from TCGA-RCC cohorts of ccRCC (A), chRCC (B) and pRCC (C) were presented. Patients were grouped into the high AKT2 expression group versus the low AKT2 expression group based on the median AKT2 mRNA expression. Each p-value for the significance from high versus low AKT2 expression was calculated using the log-rank test. The figures were performed using R version 4.0.3.

Families with a high incidence of hereditary breast cancer, and subsequently shown to have terminating mutations in BRCA1 or BRCA2, appear to have a higher incidence of prostate cancer among male relatives. We aimed to determine whether the common germline mutations of BRCA1 or BRCA2 in Ashkenazi Jewish men predisposed them to prostate cancer.We examined genomic DNA from 83 (for BRCA1 185delAG) or 82 (for BRCA2 6174delT) Ashkenazi Jewish prostate cancer patients, most of whom were treated at a relatively young age, for the most common germline mutation in each gene seen in the Ashkenazi population.Our study should have been able to detect a 4-5-fold increase in the risk of prostate cancer due to mutation of BRCA1 or BRCA2. However, only one (1.15%; 95% confidence interval, 0-3.6%) of the patients was heterozygous for the BRCA1 mutant allele, and only two were heterozygous for the BRCA2 mutation (2.4%; 95% confidence interval, 0-6.2%).The incidence of each of the germline mutations in these prostate cancer patients closely matched their incidence (about 1%) in the general Ashkenazi Jewish population. This suggests that unlike cases of breast and ovarian cancers, mutations in BRCA1 or BRCA2 do not significantly predispose men to prostate cancer.