bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B52: Loss of anterior gradient protein in high-grade prostate cancer is associated with loss of tumor cell adhesion and epithelial cell polarity
Authors: Chanda Diptiman , Sawant Anandi , Hensel Jonathan Adam , Isayeva Tatyana , Reilly Stephanie D. , Siegal Gene P. , Smith Claire , Ponnazhagan Selvarangan 
Published: May 2013

Abstract
Prostate cancer has the highest rate of incidence among all cancers in men in the United States and the second leading cause of death behind lung cancer. The human homologue of the frog (Xenopus) anterior gradient protein (AGR-2) has gained considerable attention in recent years for its putative role in neoplastic growth, metastasis and poor survival of patients with breast and prostate cancers. AGR-2 is reported to be androgen dependent and expressed only during the early stages of prostate cancer progression, whereas significant decline in AGR-2 levels in higher grades tumors coincided with metastatic disease. Human primary prostate cancer tissues and regional metastasis were immunostained for AGR-2 expression. Results indicated that AGR-2 was localized in the glandular epithelium of the prostate gland. No significant difference in AGR-2 staining was observed between normal, BPH and well-differentiated prostate cancers, except in normal prostate, where AGR-2 was mostly concentrated in the nuclei. Similar results were observed in a spontaneously developing transgenic adenocarcinoma of mouse prostate (TRAMP) model. AGR-2 expressions was reduced significantly in moderately and poorly-differentiated tumors in both human and TRAMP mice. Higher AGR-2 levels were found in the metastatic tissue albeit lower expressions in the highest grades prostate tumors within the same individual, suggesting further requirement of AGR-2 for growth at the metastatic sites. Targeted silencing of AGR-2 in a bone metastatic prostate cancer cell line, PC3, resulted in significantly reduced cellular adhesion to various extracellular matrix proteins and a failure to form acinar structures following 3-dimensional growth on matrigel. We also determined that AGR-2 silencing led to down-regulation of crucial integrins in PC3 cells, which possibly explains mechanism by which AGR-2 maintains polarized morphology of epithelial cells through promotion of cell adhesion. Based on our findings, we hypothesize that loss of AGR-2 in prostate cancer cells allows detachment from the basement membrane of the primary site and initiates metastasis. AGR-2 as well as integrin levels are restored during passage through circulation and at the metastatic site(s), helping them re-attach to the new microenvironment.
Citation Format: Diptiman Chanda, Anandi Sawant, Jonathan Adam Hensel, Tatyana Isayeva, Stephanie D. Reilly, Gene P. Siegal, Claire Smith, Selvarangan Ponnazhagan. Loss of anterior gradient protein in high-grade prostate cancer is associated with loss of tumor cell adhesion and epithelial cell polarity [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B52.
Abstract B57: Oncostatin M promotes progression of Pten-deficient prostate cancer
Authors: Smith Daniel A. , Zong Yang , Kiba Atsushi , Witte Owen N. 
Published: May 2013

Abstract
Chronic inflammation has been proposed to play a crucial role in several cancers including gastric, pancreatic, colon and lung, with recent evidence suggesting involvement in prostate cancer. While both interleukin 6 (IL6) and the related cytokine oncostatin M (OSM) have been implicated in prostate cancer, there have been few studies using in vivo models. To address this issue, we employed a dissociated prostate tissue recombination system using epithelium derived from conditional Pten knockout mice. Loss of Pten is common in prostate cancer and generates an intermediate murine prostatic intraepithelial neoplasia (mPIN) lesion in our system, providing an ideal means to assess functional synergy. We hypothesize that increased expression of these cytokines in the prostate microenvironment will promote malignant progression of intermediate prostate cancer lesions.
Paracrine expression of IL6 did not transform naïve prostate epithelium nor did it exhibit functional synergy with Pten null epithelium in our system. Grafts expressing OSM alone did not transform naïve tissue, though in contrast, presented dramatic functional synergy with loss of Pten in prostate epithelium. Loss of Pten combined with OSM exhibited progression to poorly differentiated adenocarcinoma with features of epithelial-to-mesenchymal transition (EMT). Transformed tissues displayed loss of cytokeratin expression with down-regulation and mis-localization of e-cadherin. These tumors exhibit activation of several pathways downstream of OSM signaling including STAT3 and Erk1/2 as seen by immunohistochemical analysis. Further, we interrogated the role of OSM in promoting hormone refractory prostate cancer by castrating host animals following tumor establishment. Loss of Pten alone failed to progress beyond mPIN lesions and eventually regressed at 6 months post castration. In dramatic contrast, grafts expressing the OSM ligand exhibited initial regression with castration resistant growth following a latency period, recapitulating events commonly observed in human disease.
Our evidence suggests that in the context of Pten loss, IL6 does not appear to promote prostate malignancy in the murine system. Conversely, we have identified that OSM synergizes with loss of Pten to promote aggressive prostate malignancy. Paracrine expression of OSM results in activation of several pathways, providing a means to interrogate hierarchy within signaling modules in the context of prostate cancer progression. Our study further indicates that OSM could play a role in promoting castration resistance, allowing investigation of potential points for therapeutic intervention.
Citation Format: Daniel A. Smith, Yang Zong, Atsushi Kiba, Owen N. Witte. Oncostatin M promotes progression of Pten-deficient prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B57.
Abstract B67: The epigenetic regulator Hmga2 is sufficient to initiate prostate cancer via paracrine Wnt signaling
Authors: Zong Yang , Huang Jiaoti , Witte Owen N. 
Published: May 2013

Abstract
Carcinomas result from the stepwise acquisition of multiple genetic alterations within the epithelial compartment. The surrounding stroma, including extracellular matrix, blood vasculature, inflammatory cells and fibroblasts, also plays important roles in cancer initiation and progression. Aberrant microenvironment resulting from aging and chronic inflammation as well as tumor stress can provide “field effects” to facilitate the development of multifocal malignant lesions with independent clonal origin. Given the rare frequency of genetic changes identified in cancer associated stroma, it is likely that epigenetic alterations, such as histone modifications and chromatin remodeling, could contribute to the tumor-promoting phenotype of cancer associated stromal cells. Here we utilize high-mobility group AT-hook 2 (Hmga2), a nonenzymatic epigenetic regulator, to modify prostate stromal cells, and demonstrate that perturbation of the microenvironment by stromal-specific overexpression of this chromatin remodeling protein is sufficient to induce multiple high-grade prostatic intraepithelial neoplasia lesions from adjacent naïve epithelial cells. The growth-promoting effects of Hmga2-expressing stromal cells are predominantly mediated by increased Wnt/β-catenin signaling and preferentially act on prostate stem cells-enriched basal epithelial cells. Enhancement of Hmga2-induced paracrine signaling by overexpression of androgen receptor (AR) in the stroma drives full carcinoma in the adjacent epithelial tissues, indicating that combined targeted therapies against augmented Wnt and stromal AR signaling may represent as an effective treatment strategy for prostate cancer. Our findings provide compelling evidence for the critical contribution of epigenetic changes in stromal cells to multifocal tumorigenesis, and for the first time reveal that Hmga2, a cell intrinsic oncoprotein, could exert its function via paracrine Wnt signaling.
Citation Format: Yang Zong, Jiaoti Huang, Owen N. Witte. The epigenetic regulator Hmga2 is sufficient to initiate prostate cancer via paracrine Wnt signaling [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B67.
Abstract C11: Using GCP to improve initial response to androgen deprivation in prostate cancer
Authors: Mooso Benjamin A. , Mudryj Maria , deVere White Ralph W. , Ghosh Paramita M. , Savoy Rosalinda M. , Cheung Jean P. , Vinall Ruth L. , Tepper Clifford G. , Wang Yu , Siddiqui Salma , Bedolla Roble G. , Mikhailova Margarita 
Published: May 2013

Abstract
Recurrent prostate cancer (PCa) is treated with androgen deprivation therapy (ADT, chemical castration), but patients on this treatment frequently relapse, indicative of the advent of castration resistant prostate cancer (CRPC). Due to the multifocal nature of the disease, any one treatment may not affect all pathways altered in CRPC; therefore, we set out to delay CRPC by increasing the apoptotic rate during ADT. We previously published that Filamin A (FlnA) is localized to the nucleus in androgen-dependent cells, whereas its expression is lost from the nucleus in CRPC. Restoration of FlnA nuclear expression induced apoptosis in the absence of androgens. We now show that genistein combined polysaccharide (GCP), a combination of isoflavones, can induce FlnA translocation to the nucleus. GCP and its main component genistein previously failed to prevent progression in pre-prostatectomy patients with low-grade PCa. However, our new data, both in vitro and in an animal model, show that GCP impedes relapse following castration, and induces apoptosis in PCa cells undergoing ADT, by promoting FlnA cleavage and nuclear translocation. Investigation of the mechanism of GCP's effects on FlnA showed that ADT phosphorylates FlnA and prevents its cleavage, whereas GCP inhibits FlnA phosphorylation, thereby promoting its cleavage and nuclear translocation. Additional data show that nuclear localization of FlnA induces apoptosis during ADT by preventing androgen receptor (AR) stabilization and by suppression of the ErbB3/PI3K/Akt axis. Taken together, our results identify GCP as a putative therapeutic module to prolong the effectiveness of ADT in patients with metastatic prostate cancer.
Citation Format: Benjamin A. Mooso, Maria Mudryj, Ralph W. deVere White, Paramita M. Ghosh, Rosalinda M. Savoy, Jean P. Cheung, Ruth L. Vinall, Clifford G. Tepper, Yu Wang, Salma Siddiqui, Roble G. Bedolla, Margarita Mikhailova. Using GCP to improve initial response to androgen deprivation in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C11.
Abstract C23: MicroRNA-106b targets caspase-7 and is associated with recurrence in human prostate cancer
Authors: Hudson Robert S. , Dorsey Tiffany H. , Yi Ming , Esposito Dominic , Stephens Robert M. , Croce Carlo M. , Ambs Stefan 
Published: May 2013

Abstract
Previously, we found several microRNA (miR) of the polycistronic miR-106b-25 cluster to be elevated in prostate cancer. This cluster is a homolog to the prototypical oncomiR-1 (miR-17-92) and is thought to act as a super-oncogene when co-amplified with its host gene minichromosome complex maintenance component 7 (MCM7). In this study we validated our previous findings in an independent prostate cancer dataset and further found that miR-106b is elevated in metastatic tissues and associated with disease recurrence. Genome-wide analysis of miR-106b-25 correlated transcripts revealed enrichment of focal adhesion and ECM-receptor interaction genes. Further, we found miR-106b target enrichment in transcripts that were protective against recurrence, suggesting that miR-106b targets collectively have a functionally protective role in the recurrence of prostate cancer. In cell based assays, overexpression of miR-106b increased proliferation, adhesion-free survival, soft agar survival, and adhesion to ECM components (laminin, and collagen type I and IV). In addition, microarray analysis showed that miR-106b down-regulated transcripts were enriched for miR-106b targets sites and cell death pathways genes. When we compared genes that were related to recurrence, altered by miR-106b, and predicted to have miR-106b 3′UTR target sites we identified CASP7, a central executioner of apoptosis. Corroborating these findings we found that the expression of CASP7 was consistently reduced in primary human prostate tumors and metastatic lesions across multiple prostate cancer datasets, and is by itself a candidate predictor of disease recurrence. Western blot analysis in RWPE-1, 22Rv1, and LNCaP prostate cells showed that miR-106b was capable of reducing CASP7 protein levels. Direct targeting of the CASP7 3′UTR by miR-106b was confirmed using wild-type and mutant 3′UTR luciferase reporter assays. This research reveals a novel oncogenic role for the miR-106b-25 cluster in prostate cancer and, for the first time, indentifies CASP7 as a direct target of miR-106b. Future work is aimed at understanding the role of miR-106b-dependent regulation of CASP7 and the possible utility of targeting miR-106b as novel therapy for prostate cancer.
Citation Format: Robert S. Hudson, Tiffany H. Dorsey, Ming Yi, Dominic Esposito, Robert M. Stephens, Carlo M. Croce, Stefan Ambs. MicroRNA-106b targets caspase-7 and is associated with recurrence in human prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C23.
Abstract C61: The use of beta blockers improve cancer-specific survival in prostate cancer patients receiving androgen deprivation therapy
Authors: Grytli Helene Hartvedt , Håheim Lise Lund , Taskén Kristin Austlid 
Published: May 2013

Abstract
Objective: To examine the potential effects of beta blocker use on clinical prognostic factors present at the time of prostate cancer diagnosis and on prostate cancer specific survival.
Experimental procedures: The present study is a prospective study of men who participated both in the Oslo study of 1972/73 and in a follow-up health screening in 2000 (n=6515). Self-administrated questionnaires provided information about use of beta blockers during the past four weeks before the survey in 2000 (n=776; 11.9%). Data from the 2000 survey were coupled with clinical and prognostic information from the Norwegian Cancer Registry to identify those men diagnosed with prostate cancer. Mortality data was obtained from the Norwegian Causes of Death Registry. All men diagnosed with prostate cancer that did not report the use of a beta blocker were considered the control group.
Results: Out of the 6515 men participating in the Oslo II study, a total of 655 men (10.1%) were diagnosed with prostate cancer. There was no significant differences between beta blocker users (n=80) and non users (n=575) regarding PSA, clinical T-stage, Gleason score, metastasis, or age at diagnosis. There were also no effects on prostate cancer specific survival in the group as a whole, analyzed by competing risk regression modeling (adjusted subdistribution hazard ratio (SHR) 0.69, 95% confidence interval (CI) 0.36-1.30, p = 0.252). When stratifying patients according to androgen deprivation therapy (ADT) from time of diagnosis, there was an association between beta blocker use and improved prostate cancer specific survival for men in the ADT- treated group (n=263), with an adjusted SHR of 0.18 (95% CI 0.03–0.96, p = 0.044). For patients not treated with ADT from the time of diagnosis (n=227), no difference on prostate cancer specific survival was seen (adjusted SHR 1.19, 95% CI 0.20-6.99, p = 0.844). Adjustment was made for metastasis, age at diagnosis and level of education as recorded in the 2000 screening.
Conclusion: The use of beta blockers was associated with an increased prostate cancer specific survival in men treated with ADT.
Citation Format: Helene Hartvedt Grytli, Lise Lund Håheim, Kristin Austlid Taskén. The use of beta blockers improve cancer-specific survival in prostate cancer patients receiving androgen deprivation therapy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C61.
Abstract C64: Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation
Authors: Choi Nahyun , Zhang Boyu , Zhang Li , Ittmann Michael , Xin Li 
Published: May 2013

Abstract
The prostate epithelial lineage hierarchy and the cellular origin for prostate cancer remain inadequately defined. We sought to utilize a lineage tracing approach to define the epithelial lineage hierarchy in the prostate. A previously reported K14-CreER transgenic mouse line was bred with a fluorescent reporter line to specifically label the prostate basal cell lineage. In parallel, the prostate luminal cell lineage was labeled with fluorescence using a novel K8-CreERT2 transgenic mouse line generated in our own lab. Using this lineage tracing approach, we show that adult rodent prostate basal and luminal cells are independently self-sustained in vivo.
We then sought to characterize the cells of origin for prostate cancer in the context of loss of function of Pten, which occurs frequently in primary and advanced human prostate cancer. We bred the K14-CreER and K8-CreERT2 mouse lines with Ptenfl/fl mice separately so that Pten expression can be disrupted specifically in prostate basal and luminal cells, respectively. Disrupting Pten in either lineage led to prostate cancer initiation. However, the cellular composition and onset dynamics of the resulting tumors are distinctive. Prostate luminal cells are more responsive to Pten null-induced mitogenic signaling. In contrast, basal cells are resistant to direct transformation. Instead, loss of Pten activity induces the capability of basal cells to differentiate into transformation-competent luminal cells.
These studies suggest that deregulation of the normal prostate epithelial differentiation program is a critical step for initiation of human prostate cancer with a basal cell origin. Furthermore, suppressing signaling pathways that induce basal-luminal differentiation may provide an efficient approach to prevent prostate cancer initiation.
Citation Format: Nahyun Choi, Boyu Zhang, Li Zhang, Michael Ittmann, Li Xin. Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C64.
Abstract IA1: COP1: Tumor suppressor role revealed
Authors: Dixit Vishva M. 
Published: May 2013

Abstract
Proto-oncogenes ETV1, ETV4, and ETV5 belong to the PEA3 family of ETS transcription factors and have been identified recently in prostate cancer chromosomal rearrangements that result in their overexpression. Little is known, however, about their post-translational regulation. Here we show that ETV1, ETV4, and ETV5 interact with the ubiquitin ligase COP1. COP1 together with its binding partner DET1 ubiquitinated ETV1, resulting in ETV1 proteasomal degradation. Importantly, we show that truncation of ETV1 by the TMPRSS2:ETV1 translocation found in prostate cancer removes its COP1 binding motif and thereby enhances its stability. Consistent with a critical role for COP1 in regulating PEA3 transcription factors, COP1 deficiency in primary mouse prostate cells produced prostate intraepithelial neoplasia in vivo. The relationship between COP1 and ETV1 was also evident in human prostate cancer samples where loss of COP1 expression correlated with elevated ETV1 protein.
Citation Format: Vishva M. Dixit. COP1: Tumor suppressor role revealed [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA1.
Abstract IA13: Recurrent SPOP mutations define a distinct molecular subclass of prostate cancer
Authors: Barbieri Christopher E. , Baca Sylvan C. , Lawrence Michael S. , Getz Gad , Rubin Mark A. , Garraway Levi A. ,   On the behalf of the Broad Institute and Weill Cornell Medical College Prostate Cancer Sequencing Group
Published: May 2013

Abstract
Prostate cancer is a clinically heterogeneous disease with marked variability in outcomes. To identify somatic mutations that may drive prostate cancer and aid in molecular characterization, we sequenced the exomes of 112 tumor/normal pairs obtained from men with localized disease. SPOP (Speckled Type POZ) was the most frequently mutated gene, with mutations involving the SPOP substrate binding cleft in 6-15% of tumors from multiple independent cohorts. SPOP-mutant prostate cancers lacked ETS rearrangements and exhibited a distinct pattern of genomic alterations. Thus, SPOP mutations may define a new molecular subtype of prostate cancer.
Citation Format: Christopher E. Barbieri, Sylvan C. Baca, Michael S. Lawrence, Gad Getz, Mark A. Rubin, Levi A. Garraway, On the behalf of the Broad Institute and Weill Cornell Medical College Prostate Cancer Sequencing Group. Recurrent SPOP mutations define a distinct molecular subclass of prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA13.