bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A020: Integrative analysis of the proteome in primary and advanced prostate cancer
Authors: Latonen Leena , Afyounian Ebrahim , Jylhä Antti , Nättinen Janika , Aapola Ulla , Annala Matti , Kivinummi Kati , Tammela Teuvo , Beuerman Roger W. , Uusitalo Hannu , Nykter Matti , Visakorpi Tapio 
Published: February 2019

Abstract
To fully understand the output of alterations in cancer genomes and transcriptomes, we need to know how these aberrations are translated into the functional protein units in cells. We assessed proteomic changes during disease formation and progression in prostate cancer by performing high-throughput mass spectrometry on clinical tissue samples of benign prostatic hyperplasia (BPH), untreated primary prostate cancer (PC), and castration-resistant prostate cancer (CRPC). With SWATH-MS quantitation-based proteomics we found that each of these sample groups show a distinct protein profile. By integrative analysis of this mass spectrometry dataset with genetic, epigenetic, and transcriptional data from the same samples, we show that, especially in CRPC, gene copy number, DNA methylation, and RNA expression levels do not reliably predict proteomic changes. From our analysis, we have identified sets of novel expression changes occurring primarily at the protein level, in addition to identification of several miRNA-target correlations present at protein but not at mRNA level. We find novel expression changes in previously unrecognized pathways in prostate cancer that are likely to affect disease development and progression. For example, we identify two metabolic shifts in the citric acid cycle (TCA cycle), one occurring during primary cancer development and the second during castration resistance, having implications on drug targeting against cancer metabolism. Our proteogenomic analysis of prostate cancer uncovers robustness against genomic and transcriptomic aberrations during disease progression, reveals new disease mechanisms, and significantly extends understanding of prostate cancer biology.
Citation Format: Leena Latonen, Ebrahim Afyounian, Antti Jylhä, Janika Nättinen, Ulla Aapola, Matti Annala, Kati Kivinummi, Teuvo Tammela, Roger W. Beuerman, Hannu Uusitalo, Matti Nykter, Tapio Visakorpi. Integrative analysis of the proteome in primary and advanced prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A020.
Abstract A022: Role of metallothionein in the pathogenesis of prostate cancer
Authors: Hamid Sobia , Anees Mariam 
Published: February 2019

Abstract
Metallothionein (MT) is a metal binding protein of low molecular weight. It is involved in metal homeostasis, cell differentiation, proliferation, and detoxification of heavy metals. Neoplastic transformation in prostate cancer is attributed to elevated levels of metallothionein. We studied the expression of MT in prostate tissues.
Immunohistochemistry (IHC) of 35 prostate cancer patients was performed to evaluate the expression of MT and then correlated with the expression profiles of epithelial TRAIL (Tumor necrosis factor related apoptosis inducing ligand), stromal TRAIL, decoy receptors (DcR1 and DcR2), death receptors (DR4 and DR5), nuclear factor κB (NF-κB), and FLICE inhibitory protein (FLIP). We also correlated expression patterns of these proteins using Pearson correlation with clinical histopathologic factors and determined their influence on overall survival of patients. Elevated levels of MT were observed in cancer tissues as compared to benign controls. Expression levels of epithelial TRAIL, DcR1, DcR2, DR4, DR5, NF-κB, and FLIP were also enhanced in cancer tissue samples. Age at diagnosis was significantly associated with stage (R= -0.467, p=0.046), MT (R= -0.419, p=0.012), DcR1 (R= 0.355, p=0.036) and sTRAIL (R= 0.553, p= 0.001). NF-κB significantly correlated with DR5 expression (R= 0.408, p = 0.015) in tumor tissues. Better survival was observed in patients with MT negative expression (p=0.467). Elevated levels of MT in prostate cancer patients and its positive correlation with FLIP and DcR1 depict its role as an antiapoptotic moiety. Further exploration of the role of MT in prostate cancer pathogenesis could help in establishing MT as a potential therapeutic target.
Citation Format: Sobia Hamid, Mariam Anees. Role of metallothionein in the pathogenesis of prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A022.
Abstract A031: Androgen deprivation therapy-induced TGFBI signaling promotes EMT and bone metastasis of prostate cancer
Authors: Liu Yen-Nien , Chen Wei-Yu , Tsai Yuan-Chin , Yeh Hsiu-Lien , Suau Florent , Huang Jiaoti 
Published: February 2019

Abstract
Metastatic progression in patients with prostate cancer is common despite pharmacologic inhibition of androgen receptor signaling. This drug resistance is associated with increased signaling through the transforming growth factor-β (TGF-β) signaling pathway. We found the type I/II/IV collagen-binding protein transforming growth factor-β (TGF-β)-induced (TGFBI) is an important factor in the epithelial-to-mesenchymal transition (EMT) and malignant progression of prostate cancer. We identified that an androgen-responsive gene, SPDEF, navigates between AR and TGFβ signaling during prostate cancer progression to metastasis though a physical interaction with the promoter region of the TGFBI gene. We show that loss of AR-regulated SPDEF induces TGFBI expression in prostate cancer cells, leading to drastic and aggressive physiologic changes. Furthermore, we confirmed the negative correlation between SPDEF and TGFβ singling in prostate cancer patients and demonstrated that ADT can reduce SPDEF and increase TGFβ signaling. Our results support an inhibitory role of the AR on TGFβ signaling through SPDEF-mediated suppression of TGFBI, and that disruption of this pathway promotes metastatic progression in prostate cancer.
Citation Format: Yen-Nien Liu, Wei-Yu Chen, Yuan-Chin Tsai, Hsiu-Lien Yeh, Florent Suau, Jiaoti Huang. Androgen deprivation therapy-induced TGFBI signaling promotes EMT and bone metastasis of prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A031.
Abstract A060: Repression of microRNA-338/421 by EZH2 represents a novel mechanism for SPINK1-positive prostate cancers
Authors: Bhatia Vipul , Yadav Anjali , Tiwari Ritika , Nigam Shivansh , Goel Apul , Ateeq Bushra 
Published: February 2019

Abstract
Prostate cancer (PCa) is a clinically heterogeneous disease marked by variability in patient prognosis. The intratumoral and interpatient heterogeneity formed the basis of molecular stratification of the disease. Overexpression of Serine Peptidase Inhibitor, Kazal type-1 (SPINK1), was found to be the second most recurrent (~10-15%) PCa subtype, after highly recurrent (~50%) androgen-driven TMPRSS2-ERG genetic rearrangement. Unlike amplification of ERBB2 in breast cancer, SPINK1 overexpression has not been associated with gene amplification or rearrangement. Nonetheless, molecular mechanism underlying its upregulation in cancer is poorly understood and remains a matter of conjecture.
Using in silico microRNA prediction tools, we shortlisted three miRNAs, of which miR-338-5p and miR-421 revealed an inverse correlation with SPINK1 in The Cancer Genome Atlas (TCGA) prostate adenocarcinoma RNA-Seq dataset (n=106), which was validated in our PCa specimens (n=20). Here, we showed that miR-338-5p and miR-421 post-transcriptionally regulate SPINK1 by binding to its 3′ UTR. We established that miR-338-5p and miR-421 mediate several cellular responses against SPINK1-positive cancer by inducing S-phase cell-cycle arrest, inhibiting epithelial-to-mesenchymal transition (EMT), cancer stemness, and drug resistance. Moreover, ectopic expression of miR-338-5p and miR-421 abrogates SPINK1-mediated oncogenesis, tumor growth, and distant metastases in murine xenograft model. Further, mechanistically we demonstrate that Polycomb group protein enhancer of zeste homolog 2 (EZH2) mediates epigenetic silencing by establishing histone H3K27me3 repressive marks and DNA methylation, 5’ methyl cytosine (5mC) marks on the promoters of miR-338-5p and miR-421 in SPINK1-positive subtype. Thus, restoring miR-338-5p and miR-421 expression using either epigenetic drugs or synthetic mimics could abrogate SPINK1-mediated oncogenesis by targeting multiple oncogenic pathways and eliciting anticancer pleiotropic effects.
Taken together, the present study for the first time unravels the molecular mechanism underlying SPINK1 overexpression and thereby opens up new avenues for the use of miR-338-5p and miR-421 replacement therapy for the treatment of SPINK1-positive malignancies.
Citation Format: Vipul Bhatia, Anjali Yadav, Ritika Tiwari, Shivansh Nigam, Apul Goel, Bushra Ateeq. Repression of microRNA-338/421 by EZH2 represents a novel mechanism for SPINK1-positive prostate cancers [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A060.
Abstract A062: Systemic oncolytic virotherapy for prostate cancer
Authors: Nguyen Tien , Barry Michael A. 
Published: February 2019

Abstract
Oncolytic viruses hold promise as “self-amplifying” cancer therapies wherein a virally killed cell can produce thousands of new viral “drugs” that can kill more cancer cells. Oncolytic viruses may also serve to reawaken or initiate immune responses against cancers by virtue of their abilities to lyse cells, liberate cancer antigens, and provide viral DNA and proteins as immune adjuvants. Oncolytics can also be armed with cytokine or checkpoint inhibitors to amplify antitumor immune responses. Adenoviruses (Ads) are one family of oncolytic viruses. Most human studies have used human Ad serotype 5 (Ad5). Unfortunately, most patients are already immune to Ad5, increasing the likelihood that the agent will be neutralized if used as a cancer therapy. In this work, low seroprevalence Ad6 and Ad57 oncolytic viruses were tested as intravenous therapies against distant prostate cancer sites. After prostate cell infection in vitro, Ad viruses executed these cells efficiently and generated 10,000 to 100,000 progeny infectious viruses. This genome replication also amplified transgene protein production by 100 to 1,000-fold when compared to nonreplicating Ad vectors. Ad5, Ad6, and Ad57 were injected intravenously a single time in nude mice bearing human prostate tumors, and toxicity and efficacy were assessed. Ad6 and 57 produced 30-fold lower liver damage and less toxicity than Ad5. Ad6 and Ad57 significantly repressed the growth of androgen-resistant human DU145 prostate tumors and androgen-sensitive LNCaP prostate tumors and extended survival after single intravenous injection in mice. Ad6 and Ad57 E1 protein were also modified to protect normal cells from viral oncolysis while allowing the virus to amplify and kill prostate cancer cells having perturbations in p300 and pRB pathways. These and other data suggest that targeted and untargeted low seroprevalent Ad6 and Ad57 have better efficacy and safety than the benchmark oncolytic virus Ad5 for systemic therapy of advanced prostate cancer.
Citation Format: Tien Nguyen, Michael A. Barry. Systemic oncolytic virotherapy for prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A062.
Abstract A073: Metabolism of saturated fatty acids accelerates Src-mediated prostate tumor progression
Authors: KIM SUNGJIN , Yang Xiangkun , Li Qianjin , Wu Meng , Beharry Zanna , Bartlett Michael , Bielawska Alicja , Cai Houjian 
Published: February 2019

Abstract
The association of dietary fatty acids (FAs) with the risk of aggressive prostate cancer is controversial. The mechanisms of supporting how dietary FAs promote cancer progression are largely unknown. The expression and/or activity of Src family kinases are frequently elevated in several cancers, including advanced prostate cancer. This study demonstrates that dietary FAs accelerated Src-mediated prostate tumorigenesis and prostate cancer cell growth in vivo. Additionally, high dietary fat compromised the ability of dasatinib to block the oncogenic signaling of Src kinase. Metabolism of exogenous FAs, in particular palmitic and myristic acids, increased biosynthesis of acyl-CoAs and altered ceramide levels, in particular C16:0 ceramide. The combination of these effects elevated levels of myristoylated Src, increased the amount of Src in detergent resistant membranes, and enhanced Src kinase mediated oncogenic signaling. Targeting myristoylation of Src kinase, which is required for its association at the cellular membrane, blocked high fat diet-accelerated tumorigenesis in vivo. These findings illustrate how the metabolism of saturated FAs can accelerate Src-driven prostate tumor progression and suggest that prostate cancer survivors may benefit from a diet low in saturated fat.
Citation Format: SUNGJIN KIM, Xiangkun Yang, Qianjin Li, Meng Wu, Zanna Beharry, Michael Bartlett, Alicja Bielawska, Houjian Cai. Metabolism of saturated fatty acids accelerates Src-mediated prostate tumor progression [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A073.
Abstract A084: Reprogramming of androgen receptor gene expression by ACK1/TNK2 mediated histone H4 Tyr88-phosphorylation promotes castration resistance
Authors: Mahajan Nupam , Mahajan Kiran , Lawrence Harshani , Lawrence Nicholas 
Published: February 2019

Abstract
Aberrant androgen receptor (AR) transcriptional co-activator activity underlies the onset and progression of prostate cancer (PC) to castration-resistant (CRPC) state. While anti-androgens provide immediate palliative benefits by negating AR transcriptional activity, resistance inevitably develops—either by AR gene amplification, mutation, or expression of splice variants, such as AR-V7. To achieve complete remission, ablation of AR expression appears to be the key. However, targeted inhibition of AR and AR-V7 gene expression with small-molecule inhibitors has not yet been accomplished. Recently, we uncovered a novel chromatin-regulated mechanism of AR transcriptional regulation mediated by the tyrosine kinase ACK1 (also known as TNK2). We observed that ACK1 phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex is read by H4-Y88-phosphorylation and in turn deposits the transcriptionally activating H3K4-trimethyl marks, promoting AR transcription in androgen-deficient environment. Reversal of the pY88-H4 epigenetic marks by the ACK1 inhibitor (R)-9bMS sensitized naive and enzalutamide-resistant prostate cancer cells and reduced AR and AR-V7 levels to mitigate CRPC tumor growth. Interestingly, we observed that AR itself was modified by acetylation at Lys609 residue in enzalutamide-resistant PC cells, revealing an additional mechanisms underlying castration resistance. Overall, these data reveal previously undocumented epigenetic circuitry that not only sustains AR and AR-V7 expression, but also provides mechanistic insight into rapid acquisition of resistance to antiandrogens.
Citation Format: Nupam Mahajan, Kiran Mahajan, Harshani Lawrence, Nicholas Lawrence. Reprogramming of androgen receptor gene expression by ACK1/TNK2 mediated histone H4 Tyr88-phosphorylation promotes castration resistance [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A084.
Abstract A098: Whole blood assay for rapid detection of AR-v7 in metastatic castration-resistant prostate cancer: No correlation with response to androgen-axis targeting agents
Authors: To Sarah , Kwan Edmond , Fettke Heidi , Docanto Maria , Ng Nicole , Mant Andrew , Parente Phillip , Pezaro Carmel , Horvath Lisa , Graham Lisa , Todenhofer Tilman , Azad Arun 
Published: February 2019

Abstract
Background: The expression of AR-v7 in circulating tumor cells (CTCs) of mCRPC patients potentially confers treatment resistance to AR-axis targeting agents, though recent data from the ARMOR3-SV study as well as other publications challenge this hypothesis. Due to the potential barriers of developing a reliable CTC platform, our aim was to develop a rapid assay for AR-v7 detection in patient whole blood samples.
Method: We created and optimized a whole blood quantitative real-time polymerase chain reaction assay to correlate outcomes of patients on AR-axis targeting agents with expression of AR-v7. The expression of AR-v7 mRNA in whole blood from 47 patients with mCRPC was obtained prior to commencing therapy. Each sample was run in triplicate; positivity was defined as at least two replicates reaching cycle threshold within a standard deviation between cycles of ≤ 0.25. Gene expression was correlated with PSA response rate using Fisher’s exact test.
Results: In our cohort, 10 of 47 patients (21%) were AR-v7+. Of patients commencing abiraterone or enzalutamide (37/47 patients, 79%), we observed similar response rates in the AR-v7+ (4/7) patients, compared to the AR-v7 (20/30) patients (57% vs. 66%, P=0.63; Fisher’s exact test). In two patients, early onset of acquired resistance was associated with conversion from AR-v7 to AR-v7+. AR-v7 was not detected in any of the 13 normal male controls.
Conclusion: We developed a specific assay for AR-v7 detection in whole blood from mCRPC patients. Similar PSA response rates were seen in AR-v7+ and AR-v7 patients, inconsistent with literature characterizing AR-v7 as a predictive biomarker, but in support of ARMOR3-SV data demonstrating moderate response rates to an AR-axis targeting agent in AR-v7+ patients. Future directions will include cohort expansion, interrogation of other AR variants, and examination of other clinically meaningful endpoints.
Citation Format: Sarah To, Edmond Kwan, Heidi Fettke, Maria Docanto, Nicole Ng, Andrew Mant, Phillip Parente, Carmel Pezaro, Lisa Horvath, Lisa Graham, Tilman Todenhofer, Arun Azad. Whole blood assay for rapid detection of AR-v7 in metastatic castration-resistant prostate cancer: No correlation with response to androgen-axis targeting agents [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A098.
Abstract B006: Analysis of the interaction of human herpes virus 8 and gp130 in prostate cancer risk
Authors: Henning Jill D. , Kercher Kathrine , Bunker Clareann H. , Ferrel Robert E. , Patrick Alan L. , Jenkins Frank J. 
Published: February 2019

Abstract
Prostate cancer is the most common cancer among men in the United States and is second to lung cancer as a cause of cancer death. The occurrence of prostate cancer is not uniform among different races. It is more prevalent among African Americans than either Caucasians or Asians. This increased risk for prostate cancer among men of African descent is particularly strong in the Caribbean nation of Trinidad and Tobago where the prevalence of screening-detected prostate cancer was 3-fold higher among Tobago men of African descent compared to U.S. Caucasian men. In the present study we test the hypothesis that a polymorphism in the binding domain of gp130 in association with inflammation induced by HHV-8 increases the risk of prostate cancer. As a result, Tobago men with the high-risk gp130 allele whose prostates express HHV-8 proteins have an increased risk of prostate cancer (OR=3.1, 95% C.I. 1.18-8.11). In addition, studies in B cell lines derived from Tobago men with the three different genotypes showed that IL-6 causes a significant increase in cell division based on genotype with a resulting increase in STAT-3 activation via phosphorylation. These results will also aid in defining better a treatment plan for prostatic inflammation that is a result of viral infection and will provide a better understanding of disease progression.
Citation Format: Jill D. Henning, Kathrine Kercher, Clareann H. Bunker, Robert E. Ferrel, Alan L. Patrick, Frank J. Jenkins. Analysis of the interaction of human herpes virus 8 and gp130 in prostate cancer risk [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B006.
Abstract B007: Stemness features of prostate cancer cells induced by carcinoma-associated fibroblasts
Authors: Nuñez Muriel A. , Cerda-Infante Javier , Sánchez Marianela , Sotomayor Paula , Godoy Alejandro S. , Montecinos Viviana P. 
Published: February 2019

Abstract
Introduction: Carcinoma-associated fibroblasts (CAFs) play a key role during cancer progression through several mechanisms, including the induction of the epithelial-mesenchymal transition (EMT) program, giving cancer cells the ability to initiate metastasis. As the cells progress to the mesenchymal state they acquire properties of cancer stem cells (CSC) or mesenchymal stem cell (MSC). However, the contribution of the CAFs in the acquisition of the differential stemness is largely unknown. Here, we studied the stemness features of prostate cancer cells (PC3) during the EMT program induced by fibroblasts obtained from patients with nonmetastatic prostate cancer (CAF) and bone metastatic prostate cancer (mCAF).
Materials and Methods: PC3 cells were incubated with conditioned medium (CM) of CAF and mCAF for 7,14, and 21 days to induced EMT. The presence of putative CSCs and MSCs was determined by qPCR, immunocytochemistry and Western blot for the expression of CSCs and MSCs markers, respectively, and functionally evaluated by the ability to perform adipogenic, chondrogrenic, and osteogenic differentiation (MSCs) and in vitro spheroids formation and clonogenic assay (CSCs).
Results and Discussion: Our results demonstrate that cancer cells treated with CM-CAF undergo to a partial EMT program, exhibiting certain mesenchymal traits and enriched for cancer stem cells (CSCs). On the other hand, tumor cells exposed to CM-mCAF, exhibited a full EMT conversion with the greater abilities to migrate and invade in vitro and in vivo. This suggests that CAFs and mCAFs induce differential EMT programs in prostate cancer cells, which leads them to acquire CSCs or MSC features enhancing the metastatic capabilities. (FONDECYT 1150397.)
Citation Format: Muriel A. Nuñez, Javier Cerda-Infante, Marianela Sánchez, Paula Sotomayor, Alejandro S. Godoy, Viviana P. Montecinos. Stemness features of prostate cancer cells induced by carcinoma-associated fibroblasts [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B007.