Prostate Basal Cells Research Articles

Abstract 2404: Increased mitochondrial DNA copy number occurs during prostate cancer progression and in cancer precursor lesions across multiple organs

Abstract Accurately measuring mitochondrial DNA copy number (mtDNAcn) is important for improving our understanding of cancer biology. Prior studies have revealed differences in mtDNAcn between matched bulk tumor-normal pairs from a range of different organs. However, there is little consistency across tumor types; compared to their normal tissue counterparts, some cancers appear to have increased mtDNAcn, others appear to have decreased mtDNAcn, and in others, such as prostate cancer, studies have shown contradictory results. The lack of consistency of mtDNAcn changes in tumor-normal pairs may reflect a failure to address the marked heterogeneity in mtDNAcn across different cell types within normal tissues. In addition, tumor cell heterogeneity in mtDNAcn has also not been taken into account in most prior studies, which can further confound tumor-normal comparisons. Finally, little is known about mtDNAcn alterations in cancer precursor lesions. To address these technical limitations, we combined a recently introduced quantitative in situ hybridization method with immunohistochemistry in a multiplex assay. This enabled us to measure mtDNAcn using digital image analysis in specific cell populations of interest on formalin fixed paraffin embedded (FFPE) and frozen tissue samples. We determined that normal prostate basal cells have approximately 3-fold higher mtDNA levels than normal prostate luminal cells. Compared to the adjacent normal prostate glands, we found markedly increased levels of mtDNA in high-grade prostatic intraepithelial neoplasia (HGPIN), the presumptive precursor lesions to most prostate cancers. We also found increased levels as well as heterogeneity of mtDNAcn in invasive prostate cancer lesions, and more consistently elevated levels in castration-resistant metastatic prostate cancer (CRPC). Increased mtDNA copy number was also identified by whole genome sequencing and quantitative PCR from laser capture micro-dissected human prostate tumor-normal pairs. We also observed higher mtDNAcn in two other precancer lesion types, pancreatic intraepithelial neoplasia and colorectal adenomas. Our approach represents a technological advance as it facilitates mtDNAcn measurements in a manner that preserves morphology, allowing for the evaluation of specific cell populations of interest. These findings raise the hypothesis that increased mitochondrial mass and function may drive the development of precancerous lesions in the prostate, pancreas and colon, as well as invasive prostate cancer development and progression. Citation Format: Jiayu Chen, Qizhi Zheng, Jessica L. Hicks, Levent Trabzonlu, Emmanuel S. Antonarakis, Mark C. Markowski, Samuel R. Denmeade, Busra Ozbek, Anuj Gupta, Tatianna C. Larman, Ralph H. Hruban, Sarah Wheelan, Srinivasan Yegnasubramanian, Angelo M. De Marzo. Increased mitochondrial DNA copy number occurs during prostate cancer progression and in cancer precursor lesions across multiple organs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2404.

Prostatic basal cell carcinoma treated by chemoradiation with weekly cisplatine: case report and literature review

BackgroundBasal cell carcinoma of the prostate is a relatively rare entity. Their evolution is characterized by the frequency of local and/or distant relapses. Due to their rarity, the treatment is not consensual in the literature. We report here a case of Basal cell carcinoma of the prostate in a 40-year-old patient.Case presentationOur patient initially presented an obstructive lower urinary tract symptoms with a normal initial level of prostate specific antigen (PSA) test (3.5 ng/m). The transurethral resection of the prostate (TURP) was in favor of a prostatic basal cell carcinoma with its specific anatomopathological and immunohistochemical characteristics. The prostatic MRI and thoraco-abdominal CT realized after the TURP revealed a tumoral lesion of the prostatic peripheral zone with extra-capsular extension combined with right seminal vesicle invasion and a suggestion of posterior bladder wall adherence. No evidence of visceral or nodal metastases at this point. Considering the tumor being locally advanced, a concurrent chemoradiotherapy with intensity modulated technique was indicated after a multidisciplinary meeting with a 70 Gy total target dose delivered in 35 fractions and weekly Cisplatin. A year and a half after, he developed a cerebellous metastases revealed by intracranial hypertension with no other visceral lesion and complete local remission with the disappearance of the lower urinary tract symptoms and the pain and the appearance of a prostatic atrophy. The PSA level was still on the upper limit of normal. He underwent metastasectomy, and the anatomopathological study was in favor of a cerebellous metastasis of the known BCC. The patient presented postoperatively paraparesis of lower limbs with balance problems for which he was placed in palliative care with indication of postoperative radiation therapy in case of improvement of his general condition. He did not recover and deceased three months later.ConclusionsThe prostatic basal cell carcinoma is a rare aggressive entity often non-evoked at the clinical or radiological stages because of its unspecific appearance. The diagnostic of these tumors is based on histological examination and a large immunohistochemistry panel. Given its scarity, very few data is available for locally advanced non-metastatic stages treated by radiation therapy. We assess here a good local response with concurrent chemoradiation therapy.

Smoking Is Associated With Basal Cell Hyperplasia on Prostate Biopsy Specimens.

To the best of our knowledge, no study has analyzed the association between cigarette smoking and prostate basal cell proliferation. Therefore, we sought to evaluate whether smoking status is associated with the presence of basal cell hyperplasia (BCH). We performed a retrospective analysis of 8,196 men aged 50 to 75 years with prostate-specific antigen values between 2.5 µg/mL and 10 µg/mL and prior negative biopsy who were enrolled in the (REDUCE) trial. Cigarette smoking status was divided into current, former, or never categories at enrollment. The association between smoking and baseline BCH was evaluated, with logistic regression in univariable and multivariable analysis. A total of 1,233 (15.1%) men were current smokers, 3,206 (39.1%) were former smokers, and 3,575 (45.8%) were never smokers. In univariable analysis, current smoking was associated with higher baseline BCH occurrence compared with never (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.14-3.10) and former smokers (OR, 1.77; 95% CI, 1.06-2.95). Similar results were found after adjusting for patient characteristics (current vs never smokers: OR, 1.92; 95% CI, 1.14-3.26; current vs former smokers: OR, 1.71; 95% CI, 1.01-2.91). Among men undergoing prostate biopsy, all of whom had a negative biopsy result, current smoking at enrollment was independently associated with BCH in standard peripheral zone prostate biopsies.

Activated ALK Cooperates with N-Myc via Wnt/β-Catenin Signaling to Induce Neuroendocrine Prostate Cancer.

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer with poor prognosis, and there is a critical need for novel therapeutic approaches. NEPC is associated with molecular perturbation of several pathways, including amplification of MYCN. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in the pathogenesis of neuroblastoma and other malignancies where it cooperates with N-Myc. We previously identified the first case of ALK F1174C-activating mutation in a patient with de novo NEPC who responded to the ALK inhibitor, alectinib. Here, we show that coactivation of ALK and N-Myc (ALK F1174C/N-Myc) is sufficient to transform mouse prostate basal stem cells into aggressive prostate cancer with neuroendocrine differentiation in a tissue recombination model. A novel gene signature from the ALK F1174C/N-Myc tumors was associated with poor outcome in multiple human prostate cancer datasets. ALK F1174C and ALK F1174C/N-Myc tumors displayed activation of the Wnt/β-catenin signaling pathway. Chemical and genetic ALK inhibition suppressed Wnt/β-catenin signaling and tumor growth in vitro in NEPC and neuroblastoma cells. ALK inhibition cooperated with Wnt inhibition to suppress NEPC and neuroblastoma proliferation in vitro and tumor growth and metastasis in vivo. These findings point to a role for ALK signaling in NEPC and the potential of cotargeting the ALK and Wnt/β-catenin pathways in ALK-driven tumors. Activated ALK and N-Myc are well known drivers in neuroblastoma development, suggesting potential similarities and opportunities to elucidate mechanisms and therapeutic targets in NEPC and vice versa. SIGNIFICANCE: These findings demonstrate that coactivation of ALK and N-Myc induces NEPC by stimulating the Wnt/β-catenin pathway, which can be targeted therapeutically.

De novo induction of lineage plasticity from human prostate luminal epithelial cells by activated AKT1 and c-Myc.

SummaryNeuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that either develops de novo or arises from prostate adenocarcinoma as a result of treatment resistance. Although the prostate basal cells have been shown to directly generate tumor cells with neuroendocrine features when transduced with oncogenic signaling, the identity of the cell-of-origin for de novo NEPC remains unclear. We show that the TACSTD2high human prostate luminal epithelia cells highly express SOX2 and are relatively enriched in the transition zone prostate. Both TACSTD2high and TACSTD2low luminal cells transduced by activated AKT and c-Myc can form organoids containing versatile clinically relevant tumor cell lineages with regard to the expression of AR and the neuroendocrine cell markers Synaptophysin and Chromogranin A. Tumor organoid cells derived from the TACSTD2high luminal cells are more predisposed to neuroendocrine differentiation along passaging and are relatively more castration-resistant. Knocking down TACSTD2 and SOX2 both attenuate neuroendocrine differentiation of tumor organoid cells. This study demonstrates de novo neuroendocrine differentiation of the human prostate luminal epithelial cells induced by caAKT and c-Myc and reveals an impact of cellular status on initiation of lineage plasticity.

TRIM52 positively mediates NF-κB to promote the growth of human benign prostatic hyperplasia cells through affecting TRAF2 ubiquitination

AimsBenign prostatic hyperplasia (BPH) is a progressive disease, which severely affects men's health. Here, we sought to analyze the functions and mechanism of action of the tripartite motif protein 52 (TRIM52), a novel prostate basal cell biomarker in BPH. Materials and methodsImmunohistochemistry assay was performed in sectioned human BPH tissues, BPH-1 cells, and prostate RWPE-1 cells, to detect the expressions of TRIM52 and NF-κB. Western blotting and qRT-PCR analyses were conducted to measure the relative protein and mRNA expression levels, respectively. Further, lentiviral transfection was performed in BPH-1 and RWPE-1 cells to study the overexpression and siRNA knockdown of TRIM52. Dual-luciferase reporter assay was applied to evaluate the relationship between NF-κB and TRIM52. Furthermore, CCK-8 assay and flow cytometry were employed to analyze cell proliferation and apoptosis. Key findingsTRIM52 and NF-κB levels were elevated in BPH tissues, and TRIM52 expression positively correlated with NF-κB expression. TRIM52 silencing suppressed the growth of BPH-1 cells and decreased the promoter activity of NF-κB. Moreover, the NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), suppressed TRIM52-induced proliferation of RWPE-1 cells and inhibited NF-κB promoter activity in oeTRIM52 transfected RWPE-1 cells. Silencing TRIM52 also inhibited TRAF2 ubiquitination in BPH-1 cells. Further, NF-κB promoter activity in siNC transfected cells was enhanced by the recombinant protein TNF-α and inhibited by siTRIM52. SignificanceTRIM52 accelerated the growth of BPH-1 cells by upregulating NF-κB, and TRIM52 could promote TRAF2 ubiquitination. These findings might contribute to the understanding of the biological functions and action mechanisms of TRIM52 in BPH.

A method for reliable detection of genomic point mutations based on single-cell target-sequencing

The analysis of genomic point mutations is one of the research strategies to explore the clonal evolution of tumor cells. At present, clonal evolution of tumor cells is mainly determined by bulk sampling and sequencing of different sections of the tumor. Since this approach analyzes a mixture of different cell types, it may not accurately represent the clonal evolution of specific tumor cell populations and likely miss low frequency mutations, especially when the sequencing depths are not sufficient. To address this issue, we have developed a strategy to analyze genomic point mutations from prostate basal cell carcinoma (BCC) tissues at single-cell resolution. Firstly, we optimized the single-cell whole genome amplification procedure with HepG2 cells. Then the single cells from BCC tissue were captured by a microfluidic chip of Fluidigm and processed for whole-genome amplification. Both SCUBE3 and MST1L genomic mutations were obtained by whole exome sequencing. Finally, we examined the genomic mutations through single-cell targeted amplification and Sanger sequencing. The established method successfully reconfirmed the mutations of SCUBE3 and MST1L in BCC at single cell level. The strategy established in this study could provide a useful tool for determining the clonal evolution of tumor cells based on genomic mutations at single-cell resolution.

Mutational and transcriptomic landscapes of a rare human prostate basal cell carcinoma.

As a rare subtype of prostate carcinoma, basal cell carcinoma (BCC) has not been studied extensively and thus lacks systematic molecular characterization. Here, we applied single-cell genomic amplification and RNA-Seq to a specimen of human prostate BCC (CK34βE12+ /P63+ /PAP- /PSA- ). The mutational landscape was obtained via whole exome sequencing of the amplification mixture of 49 single cells, and the transcriptomes of 69 single cells were also obtained. The five putative driver genes mutated in BCC are CASC5, NUTM1, PTPRC, KMT2C, and TBX3, and the top three nucleotide substitutions are C>T, T>C, and C>A, similar to common prostate cancer. The distribution of the variant allele frequency values indicated that these single cells are from the same tumor clone. The 69 single cells were clustered into tumor, stromal, and immune cells based on their global transcriptomic profiles. The tumor cells specifically express basal cell markers like KRT5, KRT14, and KRT23 and epithelial markers EPCAM, CDH1, and CD24. The transcription factor covariance network analysis showed that the BCC tumor cells have distinct regulatory networks. By comparison with current prostate cancer datasets, we found that some of the bulk samples exhibit basal cell signatures. Interestingly, at single-cell resolution the gene expression patterns of prostate BCC tumor cells show uniqueness compared with that of common prostate cancer-derived circulating tumor cells. This study, for the first time, discloses the comprehensive mutational and transcriptomic landscapes of prostate BCC, which lays a foundation for the understanding of its tumorigenesis mechanism and provides new insights into prostate cancers in general.

Identification of a Zeb1 expressing basal stem cell subpopulation in the prostate

The basal cell compartment in many epithelial tissues is generally believed to serve as an important pool of stem cells. However, basal cells are heterogenous and the stem cell subpopulation within basal cells is not well elucidated. Here we uncover that the core epithelial-to-mesenchymal transition (EMT) inducer Zeb1 is expressed in a prostate basal cell subpopulation. The Zeb1+ prostate epithelial cells are multipotent prostate basal stem cells (PBSCs) that can self-renew and generate functional prostatic glandular structures at the single-cell level. Genetic ablation studies reveal an indispensable role for Zeb1 in prostate basal cell development. Utilizing unbiased single-cell transcriptomic analysis of over 9000 mouse prostate basal cells, we confirm the existence of the Zeb1+ basal cell subset. Moreover, Zeb1+ epithelial cells can be detected in mouse and human prostate tumors. Identification of the PBSC and its transcriptome profile is crucial to advance our understanding of prostate development and tumorigenesis.

Basal Cell Hyperplasia Observed at Biopsy Specimens after HIFU Therapy: Implication of Stemness for Organ Regeneration

Prostatic basal cell is thought to play a pivotal role in hyperplastic change or carcinogenesis of prostate by their proliferation and stem cell transformation. We investigated stem cell transformation of basal cell hyperplasia observed at biopsy specimens after High Intensity Focused Ultrasound (HIFU) therapy for early stage prostate cancer. Patients and Methods: Basal cell hyperplasia was observed at biopsy specimens in two patients after HIFU therapy. Of these patients, one showed cancer recurrence. Specimens were studied with usual HE, and immunohistochemical studies for prostate specific antigen (PSA), stem cell markers such as CD44, CD117 (c-kit), CD133 and Vimentin. Results: Both basal cell hyperplasia cases indicated PSA (-), CD44 (++), CD117 (-), Vimentin (-) and one specimen showed CD133 (++). Basal cell hyperplasia was presumed to appear during the regeneration process of normal prostate tissue after HIFU therapy, when basal cell proliferated and transformed to acinal cells through epithelial to mesenchymal transition.

Evaluating the Differentiation Capacity of Mouse Prostate Epithelial Cells Using Organoid Culture

The prostate epithelium is comprised predominantly of basal and luminal cells. In vivo lineage tracing has been utilized to define the differentiation capacity of mouse prostate basal and luminal cells during development, tissue-regeneration and transformation. However, evaluating cell-intrinsic and extrinsic regulators of prostate epithelial differentiation capacity using a lineage tracing approach often requires extensive breeding and can be cost-prohibitive. In the prostate organoid assay, basal and luminal cells generate prostatic epithelium ex vivo. Importantly, primary epithelial cells can be isolated from mice of any genetic background or mice treated with any number of small molecules prior to, or after, plating into three-dimensional (3D) culture. Sufficient material for evaluation of differentiation capacity is generated after 7-10 days. Collection of basal-derived and luminal-derived organoids for (1) protein analysis by Western blot and (2) immunohistochemical analysis of intact organoids by whole-mount confocal microscopy enables researchers to evaluate the ex vivo differentiation capacity of prostate epithelial cells. When used in combination, these two approaches provide complementary information about the differentiation capacity of prostate basal and luminal cells in response to genetic or pharmacological manipulation.

MYB-NFIB gene fusion in prostatic basal cell carcinoma: clinicopathologic correlates and comparison with basal cell adenoma and florid basal cell hyperplasia

Prostatic basal cell carcinoma is a malignant neoplasm composed of basaloid cells forming infiltrative nests and tubules, which may potentially be misdiagnosed as benign basal cell proliferations (i.e., florid basal cell hyperplasia or basal cell adenoma) and also closely resembles adenoid cystic carcinoma of the salivary gland. MYB-NFIB gene rearrangement occurs in 30–86% of salivary gland adenoid cystic carcinomas. We sought to further characterize MYB gene rearrangement in prostatic basal cell carcinoma and correlate MYB-NFIB fusion status with other clinicopathologic characteristics. To this end, FISH analysis for MYB-NFIB gene fusion using fusion probes was performed on formalin-fixed, paraffin-embedded tissue sections from prostatic basal cell carcinoma (n = 30), florid basal cell hyperplasia (n = 18), and basal cell adenoma (n = 4). Fourteen of 30 (47%) cases of basal cell carcinoma were positive for MYB-NFIB gene fusion FISH, and no cases of benign basal cell proliferations were positive (p < 0.05). FISH-positive patients (mean age = 63 years, range: 35–81) tended to be younger than FISH-negative patients (mean age = 70 years, range: 55–93). Most FISH-positive cases demonstrated adenoid cystic carcinoma-like morphology (57%), and most FISH-negative cases demonstrated nonadenoid cystic carcinoma-like morphology (93%); one case (FISH-positive) demonstrated areas with both adenoid cystic carcinoma-like and nonadenoid cystic carcinoma-like morphology. FISH-positive cases more frequently demonstrated perineural invasion (50% vs. 14%, p < 0.05) compared to FISH-negative cases. Conversely, tall basal cells (i.e., neoplastic cells at least two times taller than wide) were more frequent in FISH-negative cases than FISH-positive cases (93% vs. 36%, p < 0.05). Approximately, 50% of prostatic basal cell carcinoma harbor MYB-NFIB gene fusion. The majority of these cases were characterized by adenoid cystic carcinoma-like morphology, perineural invasion, and lack tall basal cells. Florid basal cell hyperplasia and basal cell adenoma are negative for MYB-NFIB gene fusion.

Expansion of Luminal Progenitor Cells in the Aging Mouse and Human Prostate

SUMMARYAging is associated with loss of tissue mass and a decline in adult stem cell function in many tissues. In contrast, aging in the prostate is associated with growth-related diseases including benign prostatic hyperplasia (BPH). Surprisingly, the effects of aging on prostate epithelial cells have not been established. Here we find that organoid-forming progenitor activity of mouse prostate basal and luminal cells is maintained with age. This is caused by an age-related expansion of progenitor-like luminal cells that share features with human prostate luminal progenitor cells. The increase in luminal progenitor cells may contribute to greater risk for growth-related disease in the aging prostate. Importantly, we demonstrate expansion of human luminal progenitor cells in BPH. In summary, we define a Trop2+ luminal progenitor subset and identify an age-related shift in the luminal compartment of the mouse and human prostate epithelium.

Dreaming of a Cure

A 2016 study led by The University of Texas MD Anderson Cancer Center (https://www.nature.com/articles/ncomms10798), proved that the prostate basal cell layer contains adult stem cells which possess a unique gene expression profile resembling the deadliest form of prostate cancer. This exciting discovery opens a new line of promising treatment to combat this scourge.

Loss of the tumor suppressor, Tp53, enhances the androgen receptor-mediated oncogenic transformation and tumor development in the mouse prostate.

Recent genome analysis of human prostate cancers demonstrated that both AR gene amplification and TP53 mutation are among the most frequently observed alterations in advanced prostate cancer. However, the biological role of these dual genetic alterations in prostate tumorigenesis is largely unknown. In addition, there are no biologically relevant models that can be used to assess the molecular mechanisms for these genetic abnormalities. Here, we report a novel mouse model, in which elevated transgenic AR expression and Trp53 deletion occur simultaneously in mouse prostatic epithelium to mimic human prostate cancer cells. These compound mice developed an earlier onset of high-grade prostatic intraepithelial neoplasia and accelerated prostate tumors in comparison to mice harboring only the AR transgene. Histological analysis showed prostatic sarcomatoid and basaloid carcinomas with massive squamous differentiation in the above compound mice. RNA-sequencing analyses identified a robust enrichment of the signature genes for human prostatic basal cell carcinomas in the above prostate tumors. Master Regulator Analysis revealed SOX2 as a transcriptional regulator in prostatic basal cell tumors. Elevated expression of SOX2 and its downstream target genes were detected in prostatic tumors of the compound mice. Chromatin immunoprecipitation analyses implicate a co-regulatory role of AR and SOX2 in the expression of prostatic basal cell signature genes. Our data demonstrate a critical role of SOX2 in prostate tumorigenesis and provide mechanistic insight into prostate tumor aggressiveness and progression mediated by aberrant AR and p53 signaling pathways.

Abstract 4607: Androgen signaling is essential for prostate cancer development initiated from prostatic basal cells

Abstract Emerging evidence has shown that both prostatic basal and luminal cells are able to initiate oncogenic transformation. However, despite the diversity of tumor initiating cells, most prostate cancer cells express the androgen receptor (AR) and depend on androgens for their growth and expansion, implicating an essential role of androgen signaling in prostate tumorigenesis. Prostatic basal cells express p63 and are able to differentiate into luminal, neuroendocrine, and basal cells. In this study, we used a variety of relevant mouse models and in vivo systems to directly address the significance of androgen signaling in oncogenic transformation and tumor development initiated from prostatic p63-expressing cells. We demonstrate that activating Wnt oncogenic signaling by expressing stabilized b-catenin in prostatic p63-expressing cells is able to induce cell proliferation and the formation of atypical cell clusters in different prostatic lobes at embryonic, prepubescent, and adult stages. Intriguingly, despite the androgen insensitive nature of prostatic p63-expressing cells, androgens are still essential for these cells to grow and develop to androgen-dependent, luminal cell type prostate tumors. These findings are consistent with what have been observed in human prostate cancers, in which the majority of tumor cells are androgen-sensitive and possess luminal cell properties, providing new insight into the molecular mechanisms for prostate cancer initiation and progression. Citation Format: Yongfeng He, Erika Hooker, Eun-Jeong Yu, Gerald R. Cunha, Lan Liao, Jianming Xu, Andrew Earl, Huiqing Wu, Michael L. Gonzalgo, Zijie Sun. Androgen signaling is essential for prostate cancer development initiated from prostatic basal cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4607.

AUTHOR REPLY

Several nonmalignant histological prostate findings have been shown to be of clinical relevance. For example, we and others have shown chronic histological prostate inflammation in needle biopsies is associated with worsening prostatitis- and benign prostate hyperplasia (BPH)-related symptoms over time. 1 Nickel JC Freedland SJ Castro-Santamaria R et al. Chronic prostate inflammation predicts symptom progression in patients with chronic prostatitis/chronic pelvic pain. J Urol. 2017 Jul; 198: 122-128 Google Scholar , 2 Nickel JC Roehrborn CG Castro-Santamaria R et al. Chronic prostate inflammation is associated with severity and progression of benign prostatic hyperplasia, lower urinary tract symptoms and risk of acute urinary retention. J Urol. 2016; 196: 1493-1498 Google Scholar While basal cell hyperplasia (BCH) in the transitional zone has been associated with BPH in prior studies, the clinical significance of BCH in needle biopsies of the peripheral zone has not been previously studied in earnest. 3 Netto GJ Epstein JI. Benign mimickers of prostate adenocarcinoma on needle biopsy and transurethral resection. Surg Pathol Clin. 2008; 1: 1-41 Google Scholar , 4 Henry G. Malewska A. Mauck R. et al. Molecular pathogenesis of human prostate basal cell hyperplasia. Prostate. 2017; 77: 1344-1355 Google Scholar Although limited by a low prevalence of BCH (1.3%), the current study is one of the largest analysis of BCH and it was unable to identify any association between BCH and prostate cancer, BPH or prostatitis-related symptoms. The lower BCH prevalence in our study likely stem from the fact that: (1) our biopsies targeted the peripheral zone only, and (2) subjects with very large prostates and/or severe urinary symptoms were excluded. Moreover, data from the 4-year repeat prostate biopsies were indeed analyzed but not included in the final manuscript given the results were similar to the ones obtained using 2-year biopsy data. While it is conceivable that future studies with larger BCH samples may identify correlations between BCH and clinically meaningful outcomes, the current relevance of BCH seems to rely solely on being a differential diagnosis for high-grade prostatic intraepithelial neoplasia and prostate adenocarcinoma and, as such, may be omitted from routine pathological prostate needle biopsy reports.

MP09-20 THE DISTRIBUTION OF COMEDONECROSIS IN INTRADUCTAL VERSUS INVASIVE PROSTATE CANCER: ANALYSIS FROM A LARGE SINGLE CENTER PROSTATECTOMY SERIES

INTRODUCTION AND OBJECTIVES:Comedonecrosis has always been assigned Gleason pattern 5. Recent recommendations suggest against the grading of intraductal carcinoma. We hypothesized that prostatic adenocarcinoma with comedonecrosis may be frequently intraductal and therefore prostate cancer grading system may need to be revised.METHODS:We searched our pathology database from 2014-2018 for radical prostatectomy cases with documented comedonecrosis (specific grade patterns accounting for pattern 4 and 5 have been documented over this period). From an initial cohort of 52 cases with reported comedonecrosis, 40 cases were retrieved and had identifiable areas of comedonecrosis on additional whole mount slides prepared for immunohistochemistry. Immunohistochemical staining was performed for prostatic basal cell markers p63 and high molecular weight cytokeratin on whole-mount tumor blocks with the largest areas of comedonecrosis.RESULTS:In 24 cases (60%), the comedonecrosis was located only in intraductal carcinom...

56 - Generation of prostate basal stem cell lines from transgenic mice - proof of principle of inducible ex vivo gene deletion

56 - Generation of prostate basal stem cell lines from transgenic mice - proof of principle of inducible ex vivo gene deletion

LEADeR role of miR-205 host gene as long noncoding RNA in prostate basal cell differentiation

Though miR-205 function has been largely characterized, the nature of its host gene, MIR205HG, is still completely unknown. Here, we show that only lowly expressed alternatively spliced MIR205HG transcripts act as de facto pri-miRNAs, through a process that involves Drosha to prevent unfavorable splicing and directly mediate miR-205 excision. Notably, MIR205HG-specific processed transcripts revealed to be functional per se as nuclear long noncoding RNA capable of regulating differentiation of human prostate basal cells through control of the interferon pathway. At molecular level, MIR205HG directly binds the promoters of its target genes, which have an Alu element in proximity of the Interferon-Regulatory Factor (IRF) binding site, and represses their transcription likely buffering IRF1 activity, with the ultimate effect of preventing luminal differentiation. As MIR205HG functions autonomously from (albeit complementing) miR-205 in preserving the basal identity of prostate epithelial cells, it warrants reannotation as LEADeR (Long Epithelial Alu-interacting Differentiation-related RNA).