bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1843: Overexpression of polyisoprenylated methylated protein methyl esterase in triple negative breast cancer
Authors: Lamango Nazarius S. , Duverna Randolph , Amissah Felix , Aguilar Byron J. , Poku Rosemary A. 
Published: August 2012

Abstract
Lack of targeted, more effective therapies for triple negative breast cancer (TNBC) has necessitated the continuous search for protein biomarkers and targets for novel therapeutic development. Polyisoprenylated monomeric G-proteins such as Ras and Rab are hyperactive in about 30% of cancers and have profound effects on cell growth. Inhibition of polyisoprenylated methylated protein methyl esterase (PMPMEase) causes the death of cancer cells thus suggesting that hyperactivity of PMPMEase may result in cancers. The current studies were to address the hypothesis that PMPMEase activity is elevated in breast cancer. PMPMEase activity was determined in breast tumors and normal adjacent tissues (NAT) in snap-frozen tissues from 10 breast cancer cases. Five- to over 20-fold increases in PMPMEase activity compared to the respective NATs were detected in 8 of the 10 cases. Specific activities ranging from 0.25 ± 0.02 to 1.58 ± 0.07 nmol/h/mg were detected in the tumors compared to 0.09 nmol/h/mg or less in the NATs. Breast cancer tissue microarrays (TMAs) consisting of 125 independent breast cancer cases and NATs were analyzed for PMPMEase expression by immunohistochemistry and scored for their immunoreactive staining intensities. Intermediate to very strong immunoreactivities were detected in the breast cancer TMA core slices compared to only trace staining in those of the NATs. The mean scores ± SEM ranged from 310 ± 21, 290 ± 7, 350 ± 15, 360 ± 18, 390 ± 14, 360 ± 29, 390 ± 13, 275 ± 10 to 65 ± 10 for TNBC, ER(+), ER(+)PR(+), ER(+)HER2(+), ER(+)PR(+)HER2(+), PR(+)HER2(+), HER2(+), PR(+) and NATs, respectively. These results show that PMPMEase overexpression in breast cancer may explain the increased enzymatic activity in the tumors. PMPMEase enzymatic activity and/or immunoreactivity may serve as diagnostic procedures for breast cancer. PMPMEase may also serve as valid target for anticancer drug development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1843. doi:1538-7445.AM2012-1843
Abstract 1845: ADAM10: A new player in breast cancer progression
Authors: Mullooly Maeve , McGowan Patricia M. , Sukor Sumainizah , Madden Stephen F. , McDermott Enda , Crown John , Duffy Michael J. 
Published: August 2012

Abstract
Background: The ADAMs are a family of proteases, best known for their role in releasing the extracellular domain of transmembrane proteins. One of the ADAMs, i.e., ADAM10, is involved in the activation of 2 important signaling systems controlling cell growth, invasion and metastasis, i.e. the EGFR and NOTCH signaling systems. Because of its ability to activate both EGFR and NOTCH, ADAM10 is likely to play a role in cancer formation or progression. The aim of this study was therefore to investigate the role of ADAM10 in breast cancer and test its therapeutic potential, especially in patients with the triple-negative form of this disease. Materials and Methods: ADAM10 mRNA expression was examined in a pooled collection of publically available databases (n ∼ 4000). ADAM10 protein was examined in a cohort of 120 breast tumor extracts by ELISA. In addition, ADAM10 expression was decreased by RNAi and the effects of this on cell proliferation, invasion and migration were determined. Using the novel ADAM10 inhibitor GI254023X (GSK), we examined the effect of ADAM10 inhibition on a panel of 13 breast cancer cell lines. Results: Using the pooled collection of databases, ADAM10 mRNA was found to be significantly elevated in HER2+ breast cancer compared to other subtypes (p &lt; 0.0001). High ADAM10 mRNA expression was also observed in basal like breast cancer and was associated with poorer overall survival in this subgroup (p = 0.0196). In a cohort of 120 breast tumor extracts, ADAM10 protein was found to be significantly higher in ER-negative compared to ER-positive tumors (p = 0.005), in high grade versus low grade tumors (p &lt; 0.0001), and in younger than older women (p = 0.018). Downregulation of ADAM10 in MDA-MB-231 breast cancer cells resulted in a significant reduction in invasion (p = 0.0006) and cellular migration (p = 0.0002). Treatment of 13 breast cancer cell lines with GI254023X resulted in variable growth inhibition (from 0 to 52%). Furthermore, GI254023X significantly decreased invasion in the MDA-MB-231 cell line (p = 0.001). Conclusions: Our findings of a correlation between ADAM10 and features of aggressive disease and the fact that its downregulation/inhibition decreased growth, invasion and migration suggests that this ADAM10 protease is involved in the progression of breast cancer. Inhibition of ADAM10 with GI254023X may be a new treatment for breast cancer. Acknowledgements: The authors thank SFI and the Molecular Therapeutics for Cancer Ireland (SRC award, 08/SRC/B1410 to MTCI) for funding this work.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1845. doi:1538-7445.AM2012-1845
Abstract 1846: Cyr61 a therapeutic target for breast carcinomas
Authors: Venkatapoorna Chandra Mohan Kurapaty , Espinoza Ingrid , Park Cheol-Hong , Busby Robert , Wiley Elizabeth , Rademaker Alfred , Lupu Ruth 
Published: August 2012

Abstract
Background: Cyr61, also known as CCN1, is a survival and pro-angiogenic factor overexpressed in invasive breast tumors that promotes tumorigenicity. We investigated whether Cyr61 plays important roles in breast cancer and evaluated its potential role as a chemotherapeutical target. Methods: We analyzed Cyr61 expression in a tissue microarray from breast cancer patients consisting of primary breast carcinomas and recurrences. Cyr61 was silenced in the metastatic MDA-MB-231 cells using a Cyr61-specific short hairpin RNA (Cyr61-shRNA). The effect of Cyr61 silencing on anchorage dependent- and independent growth, migration and invasiveness was characterized in vitro. The mechanism by which Cyr61 mediates the proliferation effects was investigated. The effect of Cyr61 in tumor growth was investigated in a subcutaneous orthotopic tumor xenograft model and the histological and immunohistochemical analysis ware performed. All statistical tests were two-sided. Results: Cyr61 is highly expressed in about 47% of the metastatic breast cancer patients analyzed. The expression is higher in the recurrences than in the primary tumors. Silencing Cyr61 inhibits cell proliferation, prevents anchorage-dependent and -independent growth, and suppresses the invasive potential of the cells by inhibiting migration in vitro. We also found that silencing Cyr61 decreases the expression of its own receptor αvβ3, and decreases its signaling activities. Remarkably, the in vivo studies showed that after silencing Cyr61 the tumor burden is significantly decreased and there is poor vascularized compared to control tumors. Conclusions: Our findings provide the proof of concept that Cyr61 is a key promoter of breast cancer tumorigenicity. It should be considered as a potential target for developing therapies to breast cancers patients that overexpress Cyr61.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1846. doi:1538-7445.AM2012-1846
Abstract 1848: Expression of an androgen transporter, organic anion transporting polypeptide 1B3, impacts progression and treatment of prostate cancer
Authors: Pressler Heather M. , Sissung Tristan M. , Price Douglas K. , Figg William D. 
Published: August 2012

Abstract
Organic anion transporting polypeptides (OATPs) are membrane transporters that facilitate the movement of large substrates into cells. One family member, organic anion transporting polypeptide 1B3 (OATP1B3) is aberrantly overexpressed in prostate cancer and has been shown to influx both endogenous small molecules and chemotherapy reagents. Our hypothesis is that the OATP1B3 affects tumor growth by influxing testosterone. However, little is known about the cause of OATP1B3 expression in cancer and the impact of OATP1B3 transport on tumor growth. Therefore, we completed a study investigating putative hypoxia elements in the OATP1B3 promoter region, characterizing the impact of OATP1B3 androgen transport on prostate cancer growth, and examining the effect of OATP1B3 on the efficacy of standard prostate cancer treatments. The results showed that OATP1B3 co-localized with HIF 1-alpha in prostate cancer tissues from patients, correlated significantly to HIF1A in xenograft tumors under castration (P=0.005), and confirmed HIF-1alpha elements in the SLCO1B3 promoter region. In addition, radioactive transport assays with Xenopus oocytes showed that OATP1B3 transports testosterone and dihydrotestosterone 50- to 250-fold over passive diffusion at low physiological concentrations. A prostate cancer cell line expressing OATP1B3 grew faster than untransfected in response to androgens at all concentrations. Finally, OATP1B3 increased cell sensitivity to docetaxel treatment. In summary, these data show that hypoxia and castration increases OATP1B3 expression in cancer, OATP1B3-mediated androgen transport significantly impacts prostate cancer growth and OATP1B3 impacts the efficacy of docetaxel. These data provides evidence that OATP1B3 impacts prostate cancer growth and treatment. Future studies could screen for specific inhibitors of OATP1B3-mediated androgen transport.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1848. doi:1538-7445.AM2012-1848
Abstract 1852: Identification of the UV-inducible RNA binding protein hnRNP A18 as a new target for melanoma progression
Authors: Yang Qingyuan , Carrier France 
Published: August 2012

Abstract
Melanoma is the most dangerous form of skin cancer. If recognized and treated early, it is nearly 100 percent curable. However, invasive melanoma is hard to treat and consequently presents an extremely poor prognosis with a 5-year survival of about 6% and a median survival duration of 7.5 months. We have identified the UV-inducible RNA binding protein hnRNP A18 as a new target for melanoma progression and responses to anticancer drugs treatments. hnRNP A18 basal levels are up-regulated in melanoma cells as compared to normal melanocytes and UV radiation increases hnRNP A18 levels in 5 of the 6 melanoma cell lines we studied. More over, down regulation of hnRNP A18 reduced by more than 80% melanoma tumor growth in mice xenograft and sensitized melanoma cells to Temozolimide (TMZ) and the hypoxic mimetic agent CoCl2. In addition, levels of hnRNP A18 expression in response to UV radiation are proportional to melanoma cells capacity to survive UV-induced cellular damage. We have identified an hnRNP A18 RNA binding signature motif in the 3′ UTR of key regulatory proteins such as HDAC 8, 9, 11, HIF-1α and ATR that can confer resistance to UV induced DNA damage and hypoxic conditions. Therefore by targeting of a single molecule, hnRNP A18, it may be possible to shut down an entire network of protective proteins conferring melanoma cells, and potentially other solid tumors, growth advantage and resistance to conventional therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1852. doi:1538-7445.AM2012-1852
Abstract 1857: Intracellular protein GP128 is a novel tumor angiogenesis marker on gastric cancer cell lines and GI tissues: Ectopic expression on the cell surface defined by MS38-2.1 mAb
Authors: Li Ming , Chen XueHua , Tao ShengCe , Zhang XiaoLei , Yin Jue , Sun JianYu , Zhou YiPing , Gao JianPeng , Liu YunCheng , Zhang DongQing , Li WanBo , Hong JingXin , Lee Jeffery E. , Liu BingYa , Feng ZhenQing , Lu Mason 
Published: August 2012

Abstract
Our aim is to generate monoclonal antibodies (mAbs) against novel markers on the cancer cell surface using an innovated high throughput screening (HTS) strategy. Mixed live cells from four gastric cancer cell lines (MKN45, SGC7901, BGC823 and MKN28) were used as the immunogen for A/J mice: spleen cells were then fused with mouse SP2/0 myeloma cells to generate monoclonal antibody hybridomas. The 16 highly positive hybridoma colonies were selected from 20,000 colonies in sixty-seven 96-well plates through screening using live cell (gastric cancer cells versus normal PBMC) staining and FACS-HTS technology. Protein-A affinity purified mAbs were used to define the antigens, which were confirmed as novel biomarkers on the cancer cell surface using microarray, mass and proteomic analyses. Protein microarray analysis with the MS38-2.1 mAb identified an intracellular protein GP128 (e.g., SPRR3) as the most likely a novel cancer biomarker. The immunohistochemical profiles of MS38-2.1 mAb in GI (gastric and colorectal) cancer tissues were found to be significantly higher (P&lt;0.01) than those in normal GI tissues, and confirmed to be restricted to the small- and medium-sized blood vessels and the cancer cells. Human SPRR3 belongs to a family of small proline-rich repeat proteins that is normally expressed intracellularly. Our findings demonstrate that GP128, like SPRR3, could be ectopically expressed in the extracellular matrix in GI cancers. Conclusion: Our results demonstrate that the intracellular protein GP128 might play a role in gastrointestinal cancer development. This investigation also provides an example of identification of potential cancer biomarkers through a novel screening technique.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1857. doi:1538-7445.AM2012-1857
Abstract 1858: Targeting FoxM1 in p53-null tumors
Authors: Wang Zebin , Raychaudhuri Pradip 
Published: August 2012

Abstract
Forkhead box transcription factor FoxM1 is overexpressed in many types of human cancers and promotes tumor development in multiple ways. It is also considered as a potential target for cancer therapy. Because greater than half of the human cancers harbor p53 mutations, we investigate the effect of FoxM1-targeting in spontaneous p53-null tumors. We show that reducing FoxM1 inhibits growth of the p53 null thymic lymphoma and sarcoma cells. In addition, ablation of FoxM1 retards the growth of the p53-null tumors in mouse xenograft model. Moreover, induction of apoptotic cell death is observed in p53 null cells after deletion of FoxM1, accompanied by decreased expression of the FoxM1 target gene Survivin. The ARF26-44 peptide, which inhibits the activity of FoxM1 by targeting it to the nucleolus, is able to effectively induce apoptosis in the p53 null spontaneous tumors. Together, our observations suggest that FoxM1 functions are critical for p53-null tumors and FoxM1 is a therapeutic target of human tumors carrying loss of function p53 mutations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1858. doi:1538-7445.AM2012-1858
Abstract 1868: Response biomarkers to IGF1R and mTOR inhibitor combination therapy in ovarian carcinoma
Authors: Haines Brian B. , Wick Michael J. , Papadopoulos Kyriakos P. , Tolcher Anthony W. , Tammam Jennifer G. , Chaney Marya F. , Nebozhyn Michael , Zhang Theresa , Ebbinghaus Scot W. , Cheng Jonathan D. , Zawel Leigh , Sathyanarayanan Sriram 
Published: August 2012

Abstract
Ovarian cancer, the sixth most frequent cause of cancer death among women in the developed world, is a heterogeneous disease characterized by a diverse set of genetic alterations. These factors underscore the need for more effective treatment options accompanied by biomarker strategies to identify patients who will have a greater likelihood to respond to novel therapy. A combination strategy to target the PI3K pathway with the mTOR inhibitor ridaforolimus and anti-IGF1R antibody dalotuzumab is currently undergoing clinical development. Previous translational work has suggested that low RAS activity, as determined by a RAS gene expression signature score, and high levels of IGF1R pathway activation may enrich for response to this combination therapy. Ranking of tumors in the Moffitt tumor database with a low RAS and high IGF profile suggested that ER+ breast and ovarian cancers are enriched for these putative response biomarkers. Consistent with these observations, clinical responses were noted for several ER+ breast or ovarian cancer patients in a Phase I trial for ridaforolimus and dalotuzumab combination therapy. To provide further support for low RAS and high IGF as response biomarkers, the anti-tumor activity of ridaforolimus and dalotuzumab was assessed in 12 patient derived primary ovarian cancer xenograft models developed at START. These models have been extensively characterized by the South Texas Accelerated Research and Therapeutics (START) group for response to standard of care drugs, and the status of many commonly mutated genes in ovarian cancer. Molecular analyses of these tumors suggest that they represent a diverse cross section of ovarian cancer. Similarly, responses to ridaforolimus and dalotuzumab combination therapy ranged from minimal to significant regression. Importantly, the responsive tumor models were associated with a low RAS gene signature and a moderate to high IGF expression level. Tumors with KRAS mutations or a high RAS gene score were generally resistant to therapy. These results support the further development of low RAS and high IGF as enrichment biomarkers for ridaforolimus and dalotuzumab combination therapy in ovarian carcinoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1868. doi:1538-7445.AM2012-1868
Abstract 1874: The role of functional polymorphisms in folate metabolism on 6-mercaptopurine-mediated hematological toxicity in children with acute lymphoblastic leukemia
Authors: Patchva Dorababu , Linga Vijay Gandhi , Digumarti Raghunadharao 
Published: August 2012

Abstract
Purpose: Defective S-methylation of 6-mercarptopurine (6-MP) either due to reduced activity of thiopurine s-methyltransferase (TPMT) or due to reduced synthesis of S-adenosyl methionine (SAM) induces hematological toxicity in children undergoing 6-MP treatment for acute lymphoblastic leukemia (ALL). Recently, we have demonstrated the genetic variants of TMPT results in hematological toxicity when on 6-MP. In the current study, we have aimed to explore the role of seven functional polymorphisms in folate metabolism as pharmacogenomic determinants of 6-MP mediated toxicity. Experimental Procedures: In 126 children with ALL being treated with 6-MP, Glutamate carboxypeptidase II (GCPII) C1561T, Reduced folate carrier 1 (RFC1) G80A, cytosolic serine hydroxymethyl transferase (cSHMT) C1420T, Thymidylate synthase (TYMS) 3′-UTR ins6/del6, Methylene tetrahydrofolate reductase (MTHFR) C677T, Methionine synthase (MTR) A2756G polymorphisms were analysed by PCR-RFLP method while TYMS 5′-UTR 28 bp tandem repeat analysis was done by PCR-AFLP method. Summary: Univariate analysis showed positive association of GCPII C1561T (r= 0.23) and cSHMT C1420T (r=0.15) variants with hematological toxicity. Multi dimensionality reduction analysis confirmed synergetic gene-gene interaction between these two loci (×2=5.9, p=0.02) apart from showing an interesting tri-variate interaction i.e, RFC1 G80A/cSHMT C1420T/TYMS 5′-2R3R. RFC1 G80A showed additive interaction with cSHMT while TYMS 2R alleles showed counteracting interaction. Toxicity grade prediction model was developed using multiple linear regression approach, which showed moderate predictability of aberrations in folate metabolism and TPMT*3C (Area under the receiver operating characteristic curve=0.69) thus explaining 36% variation in toxicity. Conclusion: Aberrations in folate metabolism and TPMT*3C contribute to 36% 6-MP mediated toxicity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1874. doi:1538-7445.AM2012-1874
Abstract 1875: Identifying genetic variants contributing to cellular susceptibility to tamoxifen using a genome-wide cell-based model
Authors: Ziliak Dana , Weng Liming , Gamazon Eric R. , Im Hae Kyung , Desta Zeruesenay , Skaar Todd C. , Flockhart David A. , Huang Rong Stephanie 
Published: August 2012

Abstract
Tamoxifen is one of the most commonly used agents in the treatment and prevention of estrogen receptor positive breast cancers. Beyond the presence of hormone receptors, there are no validated predictors of tamoxifen efficacy and toxicity. Therefore, we utilized a genome-wide cell-based model to comprehensively evaluate genetic variants for their contribution to cellular susceptibility to tamoxifen. Our model incorporates multi-dimensional datasets including genome-wide genotype, gene expression, and cellular growth inhibition following treatment in lymphoblastoid cell lines from the International HapMap project. Growth inhibition was measured using AlamarBlue Assay in 60 unrelated CEU (individuals of northern and western European decedent) and 60 unrelated YRI (individuals from Ibadan, Nigeria) samples. All cell lines were treated with increasing concentrations of endoxifen, an active metabolite of tamoxifen, for 72 hours. Log2 transformed percent survival at each concentration and IC50 were used as cellular susceptibility to drug phenotypes. A step-wise genome-wide association studies were performed among SNPs, mRNA expression, and endoxifen sensitivity phenotypes. We identified 10 and 74 SNPs associated with endoxifen sensitivity through the expression of 13 and 92 genes in the separate CEU and YRI population. Interestingly 3 genes (STS, TES and SMARCA2) identified through this method are known to play a role in hormone biosynthesis pathway. Furthermore, a large portion of identified genes was found to play a role in tamoxifen sensitivity in the NCI60 cancer cell lines including CHPT1, a known tumor progression marker. This approach has made possible the identification of genetic variants/genes that have not been previously associated with tamoxifen response. Further validation of these cell-based model findings may significantly improve our ability to predict tamoxifen treatment efficacy and toxicity in breast cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1875. doi:1538-7445.AM2012-1875