bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3653: Mutational analysis of PARK2, a regulator of cyclin D1 stability, in sporadic parathyroid adenoma
Authors: Brewer Kelly , Costa-Guda Jessica , Arnold Andrew 
Published: July 2016

Abstract
The molecular mechanisms underlying the pathogenesis of sporadic parathyroid adenomas are incompletely understood. The oncoprotein cyclin D1 is overexpressed in 20-40% of sporadic parathyroid adenomas; however, known aberrations in the gene that encodes cyclin D1, CCND1, account for less than half of these cases. Genetic alterations of PARK2, which encodes the E3 ubiquitin ligase responsible for targeting cyclin D1 for degradation, have been identified as a frequent finding in a variety of human tumors. Interestingly, genetic abnormalities of PARK2 were mutually exclusive of cyclin D1 gene alterations, suggesting a common pathway in tumorigenesis. We postulate that inactivating mutations in PARK2 lead to increased stability of cyclin D1 and thereby may contribute to the development of sporadic parathyroid adenoma. We therefore sought to identify PARK2 coding region mutations in a series of sporadic parathyroid adenomas by direct DNA sequencing. The entire coding region and intron-exon boundaries of PARK2 were examined in a cohort of eighty typically presenting, sporadic parathyroid adenomas. Six known polymorphisms were identified in several of the adenomas in this series; however, none of the polymorphisms are associated with cancer, and no other cancer-associated mutations were found. The absence of intragenic mutations in PARK2 suggests that such mutations do not commonly contribute to the development of sporadic parathyroid adenoma. However, because such intragenic mutations could be rare and limited to only those samples in which overexpression of cyclin D1 cannot be explained by genetic abnormalities in the CCND1 gene, a significant role for cyclin D1 accumulation in parathyroid tumor formation due intragenic inactivating mutations of PARK2 cannot be ruled out. Further research must be conducted in order to elucidate the mechanism(s) of cyclin D1 accumulation in parathyroid adenomas in which CCND1 aberrations are not present.
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Citation Format: Kelly Brewer, Jessica Costa-Guda, Andrew Arnold. Mutational analysis of PARK2, a regulator of cyclin D1 stability, in sporadic parathyroid adenoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3653.
Abstract 3659: DIRAS1 and DIRAS2 are novel ovarian cancer tumor suppressors that regulate cell growth, motility and autophagy
Authors: Sutton Margie N. , Lu Zhen , Yang Hailing , Huang Gilbert , Wang Yan , Mao Weiqun , Bast Robert C. 
Published: July 2016

Abstract
DIRAS3 (also known as ARHI; Aplasia Ras Homolog Member I) is a potent tumor suppressor that has been well characterized for its role in ovarian cancer and autophagy. DIRAS3 is a maternally imprinted tumor suppressor gene that encodes a 26kDa GTPase which shares 60% homology to Ras and Rap. DIRAS3 is downregulated in many tumor types including ovarian cancer. DIRAS3 is downregulated by multiple mechanisms including loss of heterozygosity, transcriptional regulation by E2F1 and E2F4, hypermethylation of the second allele, and regulation by miRNAs 221 and 222. Re-expression of DIRAS3 at physiologic levels inhibits cancer cell growth, reduces motility, induces autophagy and promotes tumor dormancy. The mechanisms by which DIRAS3 induce autophagic cell death in vitro and tumor dormancy in vivo have been well characterized by previous work in our laboratory demonstrating that DIRAS3 is required for the induction of autophagy, and that upon inhibition of autophagy you can prevent outgrowth of dormant ovarian cancer cells in vivo. Interestingly, mice do not have DIRAS3 as it was lost during evolutionary rearrangement of murine chromosomes 3 and 6 nearly 60 million years ago, yet murine cells can still undergo autophagy. The DIRAS family members, DIRAS1 and DIRAS2 share 50-60% homology with DIRAS3 and are found in the murine genome. These 22kDa GTPases differ from DIRAS3 by the truncation of their N-terminal extension. Although DIRAS1 and DIRAS2 have not previously been characterized in ovarian cancer, TCGA analysis suggests that higher mRNA expression of these genes results in a survival advantage for patients with high grade serous ovarian cancer. In this study we demonstrate that re-expression of DIRAS1 and DIRAS2 inhibit ovarian cancer cell growth in vitro and induce autophagy in both human and murine cells. DIRAS1 and DIRAS2 are required for murine autophagy induced by rapamycin or amino acid starvation. Overexpression of DIRAS1 and DIRAS2 inhibits cancer cell growth and motility, and results in the inhibition of both the PI3K and Ras/MAPK signaling pathways. Thus DIRAS1 and DIRAS2 provide many of the functions of DIRAS3 in normal and malignant murine cells.
Citation Format: Margie N. Sutton, Zhen Lu, Hailing Yang, Gilbert Huang, Yan Wang, Weiqun Mao, Robert C. Bast. DIRAS1 and DIRAS2 are novel ovarian cancer tumor suppressors that regulate cell growth, motility and autophagy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3659.
Abstract 3660: ATF4 is a putative tumor suppressor gene in medullary thyroid cancer
Authors: Bagheri-Yarmand Rozita , Cote Gilbert J. , Grubbs Elizabeth G. , Williams Michelle D. , Sherman Steven I. , Gagel Robert F. 
Published: July 2016

Abstract
Medullary thyroid carcinoma (MTC) is derived from the calcitonin-producing C-cells of the thyroid gland. Oncogenic mutations of the RET proto-oncogene are found in all hereditary MTC and ∼45% of the sporadic cases. However, it is clear that additional genetic lesions contribute to the development of both RET-dependent and RET independent MTC. We analyzed 30 primary medullary thyroid cancer (MTC) tumors by comparative genomic hybridization (CGH) arrays (Agilent 244K) and a subset of those tumors by ultra-high-resolution SNP arrays (Affymetrix SNP6.0). A consistent finding with both arrays was a loss localized to 22q13.1 in 40% of tumors. This region contains the ATF4 gene and loss of this gene was validated by real time PCR.
ATF4 is a central mediator of integrated stress response pathway and activates expression of a cohort of downstream target genes known to be involved in cell survival, apoptosis, autophagy and senescence. We hypothesize that the loss of ATF4 expression contributes to MTC progression through mechanisms involving aberrant proliferation and escape from apoptosis. We present several findings to support this. First, ATF4 protein levels were found downregulated in 50% MTC tumor tissues (n = 43) and low ATF4 expression was associated with poor overall survival in MTC patients (HR = 5.015, 95% CI: 1.38-10.64), P = 0.013). A negative correlation was observed between RET and ATF4 protein expression in MTC tumors (r = -0.89, R square = 0.799, p&lt;0.0001). Second, we showed that targeted heterozygote and homozygous deletion of Atf4 in mice causes C cell hyperplasia, a precancerous lesion preceding MTC. Third, ATF4 overexpression inhibits proliferation and survival of MTC derived cell lines. ATF4 decreases RET protein levels by inducing ubiquitination and degradation of activated RET. In contrast, ATF4 depletion upregulates RET protein levels as well as RET autophosphorylation. Finally, combination treatment of tyrosine kinase inhibitor (sunitinib) and eeyarestatin that stimulates ATF4 transcription, induces apoptosis of the MTC cells in a synergistic manner through activation of ATF4 and its target genes NOXA and PUMA as well. These results suggest ATF4 as a potential tumor suppressor gene in MTC. We postulate that inactivation of ATF4 is a central impediment to induction of apoptosis in MTC tumors. Therefore, strategies to upregulate ATF4 during TKI therapy would render tumor cells exquisitely sensitive to stress induced apoptosis, offering a novel synergistic treatment.
Citation Format: Rozita Bagheri-Yarmand, Gilbert J. Cote, Elizabeth G. Grubbs, Michelle D. Williams, Steven I. Sherman, Robert F. Gagel. ATF4 is a putative tumor suppressor gene in medullary thyroid cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3660.
Abstract 3665: WAC: A candidate tumor suppressor gene in colorectal cancer
Authors: Clark Christopher R. , Conboy Caitlin , Maile Makayla , Janik Callie , Hatler Julia , Cormier Robert , Largaespada David , Starr Timothy K. 
Published: July 2016

Abstract
Our lab recently performed a DNA transposon forward genetic screen in mice that was designed to identify low-frequency mutations that contribute to colorectal cancer (CRC) initiation and progression. Results from this screen identified the WW domain-containing adaptor with coiled-coil (WAC) gene as a top DNA transposon insertion site. WAC has previously been implicated in several cellular processes including amino acid starvation-induced autophagy, golgi biogenesis, and transcription associated histone modification but has never before been linked to tumorigenesis. Transposon mutagenesis screens performed by others (Takeda et al. Nature Genetics 2015) have also identified Wac as a common insertion site, a result that further implicates WAC as a candidate CRC driver gene. Analyses of transposon insertion patterns within Wac predict loss of gene function and a role as a tumor suppressor. Soft agar colony formation assays reveal that shRNA mediated silencing of Wac cooperates with Apc mutations in mouse colorectal cells to promote cellular transformation. Additional colony formation assays using immortalized human colonic epithelial cells and the adenoma derived AAC1 cell line also shows that silencing WAC is protumorigenic. Using a zebrafish model we demonstrated that overexpression of wild type but not cancer-associated mutant forms of WAC induce expression of the cell cycle inhibitor p21, which suggests that loss of WAC may lead to uncontrolled cellular proliferation. Finally, using publicly available mutation data we determined that WAC is somatically mutated in both breast and lung cancers; a finding that indicates WAC may serve a critical tumor suppressive role in several tissues. Currently we are developing a conditional knockout mouse to further investigate the role of WAC in CRC tumor formation.
Citation Format: Christopher R. Clark, Caitlin Conboy, Makayla Maile, Callie Janik, Julia Hatler, Robert Cormier, David Largaespada, Timothy K. Starr. WAC: A candidate tumor suppressor gene in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3665.
Abstract 3667: Potential role of DUSP4 as a tumor suppressor in pancreatic cancer
Authors: Singh Chandra K. , George Jasmine , Nihal Minakshi , Ahmad Nihal 
Published: July 2016

Abstract
Pancreatic cancer remains one of the most lethal of all human malignancies, with 48,960 expected new cases and 40,560 deaths predicted in the USA in the year 2015. In order to develop novel strategies for the management of pancreatic cancer, it is of utmost importance to intensify our efforts to dissect the molecular mechanisms involved in the pathophysiology of this fatal neoplasm. Dual-specificity phosphatase-4 (DUSP4), a family member of dual-specificity phosphatases, is capable of dephosphorylating both phosphotyrosine and phosphoserine/phosphothreonine residues and possesses activity against key signaling components of the MAPK pathway that plays an important role in cancer growth. DUSP4 has been shown to be widely expressed in different tissues and implicated in cancer development, differentiation, apoptosis and inflammation. In a recent study from our laboratory that was aimed at defining the molecular targets of the anti-cancer plant-based alkaloid sanguinarine in pancreatic cancer, we identified DUSP4 as a key protein modulated by sanguinarine. Specifically, based on proteomics data and validation by qRT-PCR and immunoblot analysis, we found that sanguinarine significantly increases DUSP4 in BxPC-3 and MIA PaCa-2 pancreatic cancer cells. Indeed, an association of DUSP4 loss with cancer progression has been shown in certain cancers. However, the role of DUSP4 in pancreatic cancer is not known. This study was designed to determine the role and importance of DUSP4 in pancreatic cancer. We determined the expression profile of DUSP4 in pancreatic cancer using immunohistochemical analysis of a tissue microarray containing a variety of pancreatic cancers and normal pancreatic tissues. The DUSP4-immunostaining was microscopically imaged followed by quantification of DUSP4 protein by multispectral Vectra™ system coupled with inForm software. We found a significant downregulation of DUSP4 in human pancreatic cancer tissues, when compared to normal pancreatic tissues. Further, to understand the importance of DUSP4 in pancreatic cancer, we determined the effect of a force overexpression of DUSP4 in MIA PaCa-2 pancreatic cancer cells. We found that DUSP4 overexpression in MIA PaCa-2 cells resulted in a significant i) decrease in cell growth and proliferation, ii) clonogenic survival, and iii) induction of apoptosis. These preliminary findings suggest a potential tumor suppressive function of DUSP4 in pancreatic cancer. Further detailed studies are ongoing in our laboratory to validate the role and functional significance of DUSP4 in pancreatic cancer.
Citation Format: Chandra K. Singh, Jasmine George, Minakshi Nihal, Nihal Ahmad. Potential role of DUSP4 as a tumor suppressor in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3667.
Abstract 3672: Coordinated roles of CHD1 and SPOP in prostate cancer pathogenesis
Authors: Vasudevan Divya , Blattner Mirjam , Deonarine Lesa D. , Chen Yu , Rubin Mark A. , Barbieri Christopher E. 
Published: July 2016

Abstract
Prostate cancer (PCa) is a clinically heterogeneous disease, consequently presenting challenges while designing efficacious therapeutic strategies across diverse patient cohorts. There is an increasing need to improve our understanding of the disease by classifying PCa into distinct molecular subtypes characterized by specific genomic alterations. To this end, loss of the gene encoding chromodomain helicase DNA binding protein 1 (CHD1) represents one of the largest classes of recurrent gene deletions detected exclusively in PCa, hallmarking up to 20% of characterized tumors. CHD1 is well known to facilitate the assembly of euchromatin during transcription. Therefore, we hypothesized that loss of CHD1 would induce a significant change in overall transcription and alter prostate cell fate, promoting tumorigenesis. To confer a high degree of physiological relevance to our studies, we utilized genetically engineered mouse (GEM) models harboring prostate-specific CHD1 deletions. Since loss of CHD1 has a significant tendency to co-occur with mutations in the SPOP gene, we generated GEM models that also co-express the SPOP F133V transgene. We derived organoid lines from GEM prostates to recapitulate prostate histology in a three dimensional matrix, which allowed us to track changes at the molecular level and overall phenotype as they relate to PCa development. We found that CHD1 loss associated strongly with the presence of an increased luminal cell population compared to wild type controls. Since luminal cells are recognized to be cells of origin in PCa, this observation is consistent with the notion that CHD1 deletion represents a pro-tumorigenic event. Additionally, our data indicates that co-occurrence of CHD1 deletions and SPOP mutations may confer a growth advantage to prostate cells. The overarching goal of this study is to define the coordinated role of CHD1 loss and SPOP mutations in PCa, highlight altered signaling pathways and phenotypes, and nominate potential therapeutic strategies for patients with this PCa subtype.
Citation Format: Divya Vasudevan, Mirjam Blattner, Lesa D. Deonarine, Yu Chen, Mark A. Rubin, Christopher E. Barbieri. Coordinated roles of CHD1 and SPOP in prostate cancer pathogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3672.
Abstract 3674: MIG-6 suppresses epithelial cell proliferation via inhibiting AKT phosphorylation during endometrial tumorigenesis
Authors: Kim Tae Hoon , Yoo Jung-Yoon , Lee Jae Hee , Kim Byung Gak , Broaddus Russell R. , Jeong Jae-Wook 
Published: July 2016

Abstract
Endometrial cancer is the most frequently diagnosed malignancy of the female genital tract. Hysterectomy is typically the first line therapeutic strategy for endometrial cancer. However, there is an increasing demand for nonsurgical approaches for endometrial cancer, especially for women of reproductive age with endometrial cancer who wish to preserve their fertility. Most endometrial cancers are characterized by actively proliferating epithelial cells, increased AKT signaling and association with prolonged, unopposed E2 exposure.
Mitogen-inducible gene 6 (Mig-6) is an important mediator of progesterone receptor action in the murine uterus. As P4 achieves the inhibition of proliferation by coordinating stromal-epithelial cross-talk, we generated a mouse model in which we specifically ablate epithelial endometrial Mig-6 using Sprr2f-cre mice (Sprr2fcre+Mig-6f/f) to understand the role of epithelial Mig-6 in the uterus. Sprr2fcre+Mig-6f/f mice displayed endometrial hyperplasia upon 10 weeks of age and develop endometrial cancer by E2 treatment for 3 months. The levels of epithelial proliferation by Ki67 staining were significantly increased in epithelial cells of Sprr2fcre+Mig-6f/f mice at 10 weeks of age. The levels of phospho-AKT and phospho-S6, downstream of AKT, were remarkably higher in Sprr2fcre+Mig-6f/f mice. Interestingly, the hyperplasia exhibited by Sprr2fcre+Mig-6f/f mice was prevented by P4 treatment for 1 week in morphological and histological analysis. Aberrant activation of proliferation as well as AKT signaling was decreased in the epithelium of Sprr2fcre+Mig-6f/f mice by P4 treatment. Furthermore, we identified that MIG-6 inhibits AKT phosphorylation in human endometrial cancer cells. These data suggest that stromal P4 signaling including Mig-6 is critical in regulation of epithelial cell proliferation via regulating AKT phosphorylation during endometrial cancer development and progression.
(This work was supported by American Cancer Society Research Grant, RSG-12-084-01-TBG to J.W.J.)
Citation Format: Tae Hoon Kim, Jung-Yoon Yoo, Jae Hee Lee, Byung Gak Kim, Russell R. Broaddus, Jae-Wook Jeong. MIG-6 suppresses epithelial cell proliferation via inhibiting AKT phosphorylation during endometrial tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3674.
Abstract 3691: MDM2 but not MDM4 promotes retinoblastoma cell proliferation through p53-independent regulation of MYCN translation
Authors: Qi Donglai , Cobrinik David E. 
Published: July 2016

Abstract
Retinoblastomas can arise from cone photoreceptor precursors in response to the loss of pRB function. Some aspects of cone precursor-specific circuitry cooperate with pRB loss to initiate this process and subsequently continue to contribute to the malignancy. Intrinsic high level MDM2 expression is a key component of this circuitry and is thought to inactivate p53-mediated tumor surveillance that could otherwise be induced by aberrant cell cycle entry. However, the MDM2-related MDM4 has also been proposed to abrogate p53-mediated tumor surveillance in the absence of detectable MDM2. Here we report that high-level MDM2 but not MDM4 has a consistent, critical role in retinoblastoma cell proliferation. Reduction of MDM2 and MDM4 only weakly induced p53, yet reduction of MDM2 but not MDM4 severely impaired proliferation and survival through a p53-independent mechanism. Specifically, MDM2 up-regulated the translation of another component of the cone circuitry, MYCN, in retinoblastoma cells. These findings indicate that high-level MDM2 expression is needed in order to perform a critical p53-independent function and may obviate the need for genomic alterations to the p53 pathway in retinoblastoma cells.
Citation Format: Donglai Qi, David E. Cobrinik. MDM2 but not MDM4 promotes retinoblastoma cell proliferation through p53-independent regulation of MYCN translation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3691.
Abstract 3693: Oligomerization status of p53 serves as an indicator of sensistivity of p53 wildtype tumors to the therapeutic combination of DNA damaging agent and checkpoint inhibitor
Authors: Puli Pawan , Lipski Robert , Levesque Aime A. 
Published: July 2016

Abstract
It is well established that cell cycle arrest in response to treatment with DNA damaging agents can be abrogated in p53-defective cells by treatment with the Chk1 inhibitors, but our more recent studies have shown that some p53 wild-type tumors are also sensitive to checkpoint abrogation. Two possible explanations are cytoplasmic sequestration of p53 or a defect in p53 oligomerization. In this study, we investigated the DNA damage response and UCN-01 sensitivity of two p53 wildtype neuroblastoma cell lines: SK-N-SH, and SH-SY5Y. In order to determine the responses of these cells to DNA damage, the cells were treated with concentrations of SN38 ranging from 0-30 ng/ml. Both lines arrested in G2, S, or G1 depending upon SN38 concentration and displayed an increase in p53 levels with increasing SN38. Additionally, p53 was phosphorylated on serine 15 and serine 20 following SN38 treatment in all three cell lines, suggesting that p53 is active. In order to determine whether these cells are susceptible to UCN-01-mediated abrogation of cell cycle arrest, cell were treated with 3 ng/ml SN38 for 24 hours, followed by 25 nM UCN-01 for 6 and 24 hours. The SK-N-SH showed now sensitivity to UCN-01 treatment whereas the SH-SY5Y abrogated S arrest within 6 hours and abrogated G2 arrest within 24 hours. We also analyzed the oligomerization status of p53 using glutaraldehyde crosslinking. The SK-N-SH cells possessed levels of p53 dimers and tetramers similar to what has previously been reported in p53 wildtype MCF10A cells. The SH-SY5Y, however, had extremely low levels of dimers and tetramers. Consistent with this, only SK-N-SH showed activation of p21waf1 and repression of cyclin B in response to SN38 treatment. Previous studies have reported cytoplasmic sequestration as a mechanism of p53 inactivation in p53 wildtype neuroblastomas. In order to determine the sub-cellular distribution of p53, we prepared nuclear and cytoplasmic extracts. Both the SK-N-SH and SH-SY5Y had primarily nuclear p53. The results of this study suggest that oligomerization status may serve as an indicator of sensitivity of p53 wildtype tumors to the therapeutic combination of DNA damage agent and checkpoint inhibitor.
Citation Format: Pawan Puli, Robert Lipski, Aime A. Levesque. Oligomerization status of p53 serves as an indicator of sensistivity of p53 wildtype tumors to the therapeutic combination of DNA damaging agent and checkpoint inhibitor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3693.