Browsing by Subject "prostate cancer"

Now showing 1 - 10 of 29
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    Activation of the oncogene ERG by the Ras/ERK and PI3K/AKT pathways
    (2019-08) Willhite, Sydney; Strittmatter, Brady; Hollenhorst, Peter
    Background and Hypothesis: The TMPRSS2-ERG re-arrangement occurs in ~50% of prostate cancers and results in aberrant expression of the transcription factor ERG in the prostate. ERG is known to be activated by the Ras/ERK and PI3K/AKT pathways, however, the exact mechanism of this activation is not fully understood. The aim of this project is to identify how activation of these signaling pathways differentially effect transcription of ERG target genes. Experimental Design or Project Methods: In order to test how the Ras/ERK and PI3K/AKT pathways effect ERG target gene transcription, normal prostate epithelial cells (RWPE1) were transfected with constitutively active AKT in combination with phospho-mutants of ERG. These cell lines were then used to conduct Quantitative Reverse Transcription PCR and Western blotting of known downstream ERG target genes to identify how the activation status of these signaling pathways affected transcription and protein production. Results: Overall, our results demonstrate that ERG mediated transcription of the VIM gene, a marker of EMT, was activated by the Ras/ERK pathway and was repressed by the PI3K/AKT pathway. In addition, we found that ERG expression decreased FOXO1 protein expression in our cell lines regardless of Ras/ERK and PI3K/AKT status. Transcription and protein quantification was also measured for ERG target gene VEGFA, a critical regulator of angiogenesis. Conclusion and Potential Impact: This project helps identify the molecular mechanisms by which a common oncogene in prostate cancer is activated. Our results demonstrate how upstream signaling pathways differentially regulate oncogenic transcription and cell transformation. Overall, this project will provide insight to the molecular mechanisms of possible therapeutic targets in prostate cancer, the most common cancer amongst men.
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    Associations between lifestyle factors and quality of life among older long-term breast, prostate, and colorectal cancer survivors
    (Wiley, 2009) Mosher, Catherine E.; Sloane, Richard; Morey, Miriam C.; Snyder, Denise Clutter; Cohen, Harvey J.; Miller, Paige E.; Demark-Wahnefried, Wendy
    BACKGROUND: Older cancer survivors are at increased risk for secondary cancers, cardiovascular disease, obesity, and functional decline and, thus, may benefit from health-related interventions. However, to the authors' knowledge, little is known regarding the health behaviors of older cancer survivors and the associations of those behaviors with quality-of-life outcomes, especially during the long-term post-treatment period. METHODS: In total, 753 older (aged ≥65 years) long-term survivors (≥5 years postdiagnosis) of breast, prostate, and colorectal cancer completed 2 baseline telephone interviews to assess their eligibility for a diet and exercise intervention trial. The interviews assessed exercise, diet, weight status, and quality of life. RESULTS: Older cancer survivors reported a median of 10 minutes of moderate-to-vigorous exercise per week, and only 7% had Healthy Eating Index scores >80 (indicative of healthful eating habits relative to national guidelines). Despite their suboptimal health behaviors, survivors reported mental and physical quality of life that exceeded age-related norms. Greater exercise and better diet quality were associated with better physical quality-of-life outcomes (eg, better vitality and physical functioning; P < .05), whereas greater body mass index was associated with reduced physical quality of life (P < .001). CONCLUSIONS: The current results indicated a high prevalence of suboptimal health behaviors among older, long-term survivors of breast, prostate, and colorectal cancer who were interested in lifestyle modification. In addition, the findings pointed to the potential negative impact of obesity and the positive impact of physical activity and a healthy diet on physical quality of life in this population. Cancer 2009.
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    CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer: implications for epigenetic therapy
    (American Association for Cancer Research, 2014-04-01) Ding, Liya; Chen, Shuai; Liu, Ping; Pan, Yunqian; Zhong, Jian; Regan, Kevin M.; Wang, Liguo; Yu, Chunrong; Rizzardi, Tony; Cheng, Liang; Zhang, Jun; Schmechel, Stephen C.; Cheville, John C.; van Deursen, Jan; Tindall, Donald J.; Huang, Haojie; Department of Pathology & Laboratory Medicine, IU School of Medicine
    Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbppc−/−;Ptenpc+/− mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp−/−;Pten+/− and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones, in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27KIP1 and p21CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbppc−/−;Ptenpc+/− mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic targeted therapy in prostate cancer patients.
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    Cholesterol Sulfonation Enzyme, SULT2B1b, Modulates AR and Cell Growth Properties in Prostate Cancer
    (AACR Publications, 2016-09) Vickman, Renee E.; Crist, Scott A.; Kerian, Kevin; Eberlin, Livia; Cooks, R. Graham; Burcham, Grant N.; Buhman, Kimberly K.; Hu, Chang-Deng; Mesecar, Andrew D.; Cheng, Liang; Ratliff, Timothy L.; Pathology and Laboratory Medicine, School of Medicine
    Cholesterol accumulates in prostate lesions and has been linked to prostate cancer (PCa) incidence and progression. However, how accumulated cholesterol contributes to PCa development and progression is not completely understood. Cholesterol sulfate (CS), the primary sulfonation product of cholesterol sulfotransferase (SULT2B1b), accumulates in human prostate adenocarcinoma and precancerous prostatic intraepithelial neoplasia (PIN) lesions compared to normal regions of the same tissue sample. Given the enhanced accumulation of CS in these lesions, it was hypothesized that SULT2B1b-mediated production of CS provides a growth advantage to these cells. To address this, PCa cells with RNAi-mediated knockdown (KD) of SULT2B1b were used to assess the impact on cell growth and survival. SULT2B1b is expressed and functional in a variety of prostate cells and the data demonstrate that SULT2B1b KD, in LNCaP and other androgen-responsive (VCaP and C4-2) cells, results in decreased cell growth/viability and induces cell death. SULT2B1b KD also decreases androgen receptor (AR) activity and expression at mRNA and protein levels. While AR overexpression has no impact on SULT2B1b KD-mediated cell death, addition of exogenous androgen is able to partially rescue the growth inhibition induced by SULT2B1b KD in LNCaP cells. These results suggest that SULT2B1b positively regulates the AR either through alterations in ligand availability or by interaction with critical co-regulators that influence AR activity.
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    COEXISTING PROSTATE CANCER FOUND AT THE TIME OF HOLMIUM LASER ENUCLEATION OF THE PROSTATE FOR BENIGN PROSTATIC HYPERPLASIA: PREDICTING ITS PRESENCE AND GRADE IN ANALYZED TISSUE
    (Liebert, 2015-01) Bhojani, Naeem; Boris, Ronald S.; Monn, M. Francesca; Mandeville, Jessica A.; Lingeman, James E.; Department of Urology, IU School of Medicine
    Objective: To determine the incidence of prostate cancer identified on holmium laser enucleation of the prostate (HoLEP) specimens and evaluate variables associated with prostate cancer identification. Patients and Methods: All patients undergoing HoLEP between 1998 and 2013 were identified. Patients with a known history of prostate cancer were excluded. Multivariable logistic regression assessed variables associated with identification of prostate cancer on HoLEP specimens and Gleason 7 or higher prostate cancer among the malignant cases. The Gleason grade was used as a proxy for disease severity. Each of the models was adjusted for age, preoperative prostate-specific antigen (PSA), and HoLEP specimen weight. Results: The cohort comprised 1272 patients, of whom 103 (8.1%) had prostate cancer identified. Prostate cancer cases had higher pre-HoLEP PSA (p=0.06) but lower HoLEP specimen weight (p=0.01). On multivariate logistic regression, age and preoperative PSA were associated with increased odds of prostate cancer being present (p<0.01 each), while increasing HoLEP specimen weight was associated with decreased odds of prostate cancer (p<0.001). Men older than 80 had 20% predicted probability of being diagnosed with prostate cancer. Seventy-eight percent of prostate cancer cases were Gleason 6 or less. The pre-HoLEP PSA was associated with increased adjusted odds of intermediate- or high-grade prostate cancer. Conclusion: Prostate cancer identified by HoLEP is not uncommon, but is generally a low-risk disease. Older patients with smaller prostate glands have the highest odds of prostate cancer identification.
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    Comparison of MAPK specificity across the ETS transcription factor family identifies a high-affinity ERK interaction required for ERG function in prostate cells
    (BioMed Central, 2015-02) Selvaraj, Nagarathinam; Kedage, Vivekananda; Hollenhorst, Peter C.; Department of Medical Sciences, IU School of Medicine
    Background The RAS/MAPK signaling pathway can regulate gene expression by phosphorylating and altering the function of some, but not all, ETS transcription factors. ETS family transcription factors bind similar DNA sequences and can compete for genomic binding sites. However, MAPK regulation varies across the ETS family. Therefore, changing the ETS factor bound to a cis-regulatory element can alter MAPK regulation of gene expression. To understand RAS/MAPK regulated gene expression programs, comprehensive knowledge of the ETS family members that are MAPK targets and relative MAPK targeting efficiency across the family is needed. Results An in vitro kinase assay was used to rank-order 27 human ETS family transcription factors based on phosphorylation by ERK2, JNK1, and p38α. Many novel MAPK targets and specificities were identified within the ETS family, including the identification of the prostate cancer oncoprotein ERG as a specific target of ERK2. ERK2 phosphorylation of ERG S215 required a DEF docking domain and was necessary for ERG to activate transcription of cell migration genes and promote prostate cell migration. The ability of ERK2 to bind ERG with higher affinity than ETS1 provided a potential molecular explanation for why ERG overexpression drives migration of prostate cells with low levels of RAS/ERK signaling, while ETS1 has a similar function only when RAS/ERK signaling is high. Conclusions The rank ordering of ETS transcription factors as MAPK targets provides an important resource for understanding ETS proteins as mediators of MAPK signaling. This is emphasized by the difference in rank order of ERG and ETS1, which allows these factors to have distinct roles based on the level of RAS/ERK signaling present in the cell.
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    Dietary intake of isoflavones and coumestrol and the risk of prostate cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial
    (Wiley, 2018-02) Reger, Michael K.; Zollinger, Terrell W.; Liu, Ziyue; Jones, Josette F.; Zhang, Jianjun; Epidemiology, School of Public Health
    Experimental studies have revealed that phytoestrogens may modulate the risk of certain sites of cancer due to their structural similarity to 17β‐estradiol. The present study investigates whether intake of these compounds may influence prostate cancer risk in human populations. During a median follow up of 11.5 years, 2,598 cases of prostate cancer (including 287 advanced cases) have been identified among 27,004 men in the intervention arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Dietary intake of phytoestrogens (excluding lignans) was assessed with a food frequency questionnaire. Cox proportional hazards regression analysis was performed to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for dietary isoflavones and coumestrol in relation to prostate cancer risk. After adjustment for confounders, an increased risk of advanced prostate cancer [HR (95% CI) for quintile (Q) 5 vs. Q1] was found for the dietary intake of total isoflavones [1.91 (1.25–2.92)], genistein [1.51 (1.02–2.22), daidzein [1.80 (1.18–2.75) and glycitein [1.67 (1.15–2.43)] (p‐trend for all associations ≤0.05). For example, HR (95% CI) for comparing the Q2, Q3, Q4 and Q5 with Q1 of daidzein intake was 1.45 (0.93–2.25), 1.65 (1.07–2.54), 1.73 (1.13–2.66) and 1.80 (1.18–2.75), respectively (p‐trend: 0.013). No statistically significant associations were observed between the intake of total isoflavones and individual phytoestrogens and non‐advanced and total prostate cancer after adjustment for confounders. This study revealed that dietary intake of isoflavones was associated with an elevated risk of advanced prostate cancer.
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    Emerging immunotherapeutic strategies targeting telomerases in genitourinary tumors
    (Elsevier, 2018) Carrozza, Francesco; Santoni, Matteo; Piva, Francesco; Cheng, Liang; Lopez-Beltran, Antonio; Scarpelli, Marina; Montironi, Rodolfo; Battelli, Nicola; Tamberi, Stefano; Pathology and Laboratory Medicine, School of Medicine
    Telomerase activity and telomere length are essential for the pathogenesis of several human diseases, including genitourinary tumors. Telomerase constitutes a complex system that includes human telomerase reverse transcriptase (hTERT), human telomerase RNA component (hTR) and telomerase associated protein 1 (TEP1), which are overexpressed in tumor cells compared to normal cells and are involved in the carcinogenesis and progression of renal cell carcinoma (RCC), bladder (BC) and prostate cancer (PCa). In addition, telomerase degraded peptide fragments expressed on the surface of tumor cells lead to their recognition by immune cells. On this scenario, in vitro and in vivo studies have shown effective anti-tumor activity of hTERT-tailored strategies in genitourinary tumors, including active immunotherapy with hTERT-peptide vaccines and passive immunotherapy with hTERT-transduced T cell infusion. This review emphasizes the role of telomerase in the carcinogenesis and progression of genitourinary tumors, thus underlying the potential of emerging telomerase-tailored immunotherapies in these patients.
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    Gene Fusion Characterization of Rare Aggressive Prostate Cancer Variants ‐ Adenosquamous Carcinoma, Pleomorphic Giant Cell Carcinoma, and Sarcomatoid Carcinoma: An Analysis of 19 Cases
    (Wiley, 2020) Alhamar, Mohamed; Vladislav, I. Tudor; Smith, Steven C.; Gao, Yuan; Cheng, Liang; Favazza, Laura A.; Alani, Ali M.; Ittmann, Michael M.; Riddle, Nicole D.; Whitely, Lisa J.; Gupta, Nilesh S.; Carskadon, Shannon; Gomez-Gelvez, Juan C.; Chitale, Dhananjay A.; Palanisamy, Nallasivam; Hes, Ondrej; Trpkov, Kiril; Williamson, Sean R.; Pathology and Laboratory Medicine, School of Medicine
    Aims We evaluated the molecular underpinnings of rare aggressive prostate cancer variants adenosquamous, pleomorphic giant cell, and sarcomatoid carcinomas. Methods and Results We retrieved 19 tumors with one or more variant(s) and performed ERG immunohistochemistry, a next‐generation sequencing assay targeting recurrent gene fusions, and fluorescence in situ hybridization (FISH) for ERG and BRAF. Divergent differentiation included: sarcomatoid (n=10), adenosquamous (n=7), and pleomorphic giant cell carcinoma (n=7). Five patients had more than one variant. Four had variants only in metastases. ERG rearrangement was detected in 9 (47%, 7 via sequencing, showing TMPRSS2‐ERG and one GRHL2‐ERG fusion, and 2 via FISH, showing rearrangement via deletion). Of these, ERG immunohistochemistry was positive in the adenocarcinoma for 8/9 (89%) but only 5/9 (56%, typically decreased) in the variant. One patient had false‐positive ERG immunohistochemistry in the sarcomatoid component despite negative FISH. Two (11%) harbored BRAF fusions (FAM131A‐BRAF and SND1‐BRAF). Conclusions ERG gene fusions are present in these rare prostate cancer variants with a close frequency to conventional prostate cancer (9/19, 47%). ERG immunohistochemistry usually detects rearrangement in the adenocarcinoma but is less sensitive for the variant histology with weak to negative staining. Adenosquamous and sarcomatoid variants particularly can occur together. Molecular assessment may be an additional tool in select cases to confirm prostatic origin of unusual tumors. The presence of 2 BRAF gene rearrangements suggests that this gene fusion may be enriched in this setting, as RAF kinase fusions have been previously reported in 1‐2% of prostate cancers.
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    Gleason Grade 4 Prostate Adenocarcinoma Patterns: An Inter-observer Agreement Study among Genitourinary Pathologists
    (Wiley, 2016-09) Kweldam, Charlotte F.; Nieboer, Daan; Algaba, Ferran; Amin, Mahul B.; Berney, Dan M.; Billis, Athanase; Bostwick, David G.; Bubendorf, Lukas; Cheng, Liang; Compérat, Eva; Delahunt, Brett; Egevad, Lars; Evans, Andrew J.; Hansel, Donna E.; Humphrey, Peter A.; Kristiansen, Glen; van der Kwast, Theodorus H.; Magi-Galluzzi, Cristina; Montironi, Rodolfo; Netto, George J.; Samaratunga, Hemamali; Srigley, John R.; Tan, Puay H.; Varma, Murali; Zhou, Ming; van Leenders, Geert J. L. H.; Department of Pathology and Laboratory Medicine, IU School of Medicine
    Aims To assess the interobserver reproducibility of individual Gleason grade 4 growth patterns. Methods and results Twenty-three genitourinary pathologists participated in the evaluation of 60 selected high-magnification photographs. The selection included 10 cases of Gleason grade 3, 40 of Gleason grade 4 (10 per growth pattern), and 10 of Gleason grade 5. Participants were asked to select a single predominant Gleason grade per case (3, 4, or 5), and to indicate the predominant Gleason grade 4 growth pattern, if present. ‘Consensus’ was defined as at least 80% agreement, and ‘favoured’ as 60–80% agreement. Consensus on Gleason grading was reached in 47 of 60 (78%) cases, 35 of which were assigned to grade 4. In the 13 non-consensus cases, ill-formed (6/13, 46%) and fused (7/13, 54%) patterns were involved in the disagreement. Among the 20 cases where at least one pathologist assigned the ill-formed growth pattern, none (0%, 0/20) reached consensus. Consensus for fused, cribriform and glomeruloid glands was reached in 2%, 23% and 38% of cases, respectively. In nine of 35 (26%) consensus Gleason grade 4 cases, participants disagreed on the growth pattern. Six of these were characterized by large epithelial proliferations with delicate intervening fibrovascular cores, which were alternatively given the designation fused or cribriform growth pattern (‘complex fused’). Conclusions Consensus on Gleason grade 4 growth pattern was predominantly reached on cribriform and glomeruloid patterns, but rarely on ill-formed and fused glands. The complex fused glands seem to constitute a borderline pattern of unknown prognostic significance on which a consensus could not be reached.