bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3734: Alcohol consumption and breast cancer risk among Nigerian women
Authors: Hou Ningqi , Ogundiran Temidayo O. , Adebamowo Clement A. , Olopade Olufunmilayo I. , Huo Dezheng
Published: June 2012

Background: Alcohol consumption has been reported as a risk factor for breast cancer. However, little is known about its importance for indigenous African population, among whom the prevalence of breast cancer is relatively low. The purpose of this study was to investigate the relationship between alcohol drinking and breast cancer risk in Nigerian women.

Methods: The study was based on the Nigerian Breast Cancer Study, a case-control study of breast cancer conducted in Ibadan, Nigeria, between 1998 and 2010. In-person interviews were conducted with 1355 invasive breast cancer cases and 1132 community controls, using structured questionnaires to collect detailed epidemiologic data including alcohol drinking. Multivariate logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI), controlling for age, ethnicity, and type of questionnaire (we revised the questionnaire in the middle of study), with potential effect measure modifications tested.

Results: 5.8% controls and 11.3% cases reported drinking alcohol every week for at least 6 months, with crude OR=2.08 (95% CI: 1.54-2.82, p<0.0001). After adjusting for potential confounding variables, alcohol drinking remained statistically associated with breast cancer risk but the strength of association was attenuated (adjusted OR=1.56, 95% CI: 1.11-2.19, p=0.01). Among women who drink weekly, the average drinks per week were 1.7±0.8 in controls and 3.4±5.8 in cases, and there was a dose-response trend: the crude OR was 1.86 for women who had 1-2 drinks per week and 3.27 for those who had ≥ 2 drinks per week, compared with non-drinkers (p-trend=0.08). The age- and ethnicity-adjusted ORs for 1-2 drinks and ≥ 2 drinks per week were 1.20 (95% CI: 0.49-2.93) and 1.80 (95% CI: 0.36-8.87), respectively. The association between alcohol drinking and breast cancer was particularly stronger in overweight or obese women who have BMI ≥ 25 kg/m2 (adjusted OR=1.92, 95% CI: 1.23-3.01, p=0.004) than in normal weight women (adjusted OR=1.20, 95% CI: 0.71-2.02, p=0.5). Similar association was observed in pre-menopausal and post-menopausal women.

Conclusions: Our study showed that regular alcohol intake is uncommon among Nigerian women. However, regular alcohol drinking may increase breast cancer risk among the Nigerians, particularly overweight women.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3734. doi:10.1158/1538-7445.AM2011-3734
Abstract 3736: Correlates of vitamin D: A measurement pilot study
Authors: Steffen Alana D. , Gies Peter , Cooney Robert
Published: June 2012

Vitamin D has protective effects for colorectal cancer and possible benefits for breast and ovarian cancers yet the determinants of vitamin D status are not fully understood. This study measured sun exposure, sun protection, diet, body mass index, and skin color and correlated them with serum 25(OH)D to understand better the impact of these factors on vitamin D status. Women (n=28) ages 18-30 residing in Hawaii attended small group sessions where they completed questionnaires about diet, supplement use, and skin type and had skin color measured by reflectance spectrophotometry. Participants wore polysulphone dosimeters mounted on wristbands, photographed clothing outfits and kept daily diaries for the 7 days before their blood draw. Results: Participants were, on average, 24.6 (3.3) years old, had BMI of 23.6 (range 17.7 – 34.7), consumed 308 IU vitamin D daily (range 10 – 1202), used sunscreen on 12% of their body (range 0 to 44%), were 44% covered by clothing (range 22 – 79%), received 2.3 standard erythemal doses (range .1 to 5.9) of UVB and had 34.7 ng/mL of 25(OH)D3 (range 17.7 – 90.5). Personal UVB dose accounted for 22% of the variance in 25(OH)D, and the addition of clothing and sunscreen coverage increased the R2 value to 0.33. Skin color and diet were not associated with 25(OH)D. While BMI was showed an association 25(OH)D, it did not improve the model and was inversely related to UVB exposure. While the measured sun-related variables were useful for predicting 25(OH)D, the majority of variance in vitamin D status is unexplained. More research is needed to understand how this hormone is regulated in the body.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3736. doi:10.1158/1538-7445.AM2011-3736
Abstract 3746: Prostate stem cell antigen is associated with gastric cancer in Caucasians: Results from the EPIC-EURGAST study
Authors: Sala Nuria , Muñoz Xavier , Travier Noemie , Agudo Antonio , Duell Eric J. , Moreno Victor , Garcia Nadia , Capella Gabriel , Riboli Elio , Gonzalez Carlos A.
Published: June 2012

Background. A genome-wide study performed in a Japanese population identified a strong association between SNP rs2294008 (Met1Thr) in the Prostate Stem Cell Antigen gene (PSCA) and diffuse-type gastric cancer (GC). This association has been validated in different Asian populations but no study has yet been conducted in Caucasians. Objective. To analyze the association between PSCA variants and gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods. As part of a wider study in which we used the Illumina GoldenGate technology to genotype 1287 SNPs in 249 candidate genomic regions, we genotyped six tagSNPs covering the PSCA gene region in 411 incident gastric adenocarcinoma cases and 1530 matched controls from a nested case-control study in the European EPIC cohort. Among GC cases, 28% were in the cardia or in the gastroesophageal junction, 48% were noncardia and 24% were unspecified. Regarding the histological type, 36% were intestinal, 35% were diffuse and 29% were unspecified. After quality control analysis and data filtering, association was analyzed by unconditional logistic regression, adjusting for age, sex and country. Results. The T allele of rs2294008 in PSCA (frequency of 0.44 in controls and 0.53 in cases) was found to be a significant risk factor for GC (per allele OR=1.42, 95%CI:1.23-1.6; uncorrected p-value=6.5×10-6; Bonferroni adjusted p-value=0.0126). The A allele of rs12155758 also appeared to increase GC risk, while the C allele of rs9297976, in LD with rs2294008, was inversely associated with GC. These 3 SNPs jointly cover 92% of the common variation (MAF≥0.05) within 10 kb around PSCA in Caucasians. Haplotype analysis did not provide additional information. No statistically significant differences were observed in the effect of rs2294008 between diffuse (OR=1.54, 95%CI:1.20-1.96; p-value=0.0005) and intestinal-types (OR=1.52, 95%CI:1.20-1.93; p-value=0.0005), or between cardia (OR=1.19, 95%CI:0.91-1.56; p-value=0.20) and noncardia (OR=1.47, 95%CI:1.19-1.81; p-value=0.0003) sub-sites, although the associations were stronger in noncardia GC. Conclusions. Variation in the promoter region of PSCA, specifically the functional rs2294008 variant, is associated with GC risk in Caucasians.

Supported by “LaCaixa” (BM06-130-0); Spanish Ministry of Health (PI070130 and PI081420); European Commission FP5 (ref.QLG1-CT-2001-01049).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3746. doi:10.1158/1538-7445.AM2011-3746
Abstract 3750: Body mass index and obesity- and diabetes-associated genotypes and risk for pancreatic cancer
Authors: Tang Hongwei , Dong Xiaoqun , Hassan Manal M. , Abbruzzese James L. , Li Donghui
Published: June 2012

Background: There is accumulating evidence that obesity and diabetes are modifiable risk factors for pancreatic cancer. However, the genetic factors predispose individuals with obesity or diabetes to pancreatic cancer has not been identified.

Aims: To investigate the hypothesis that obesity- and diabetes-related genes modify the risk of pancreatic cancer.

Methods: We genotyped 15 single nucleotide polymorphisms (SNPs) of the fat mass and obesity associated (FTO), peroxisome proliferators-activated receptor gamma (PPARγ), nuclear receptor family 5 member 2 NR5A2 (aka liver receptor homolog 1), AMP-activated protein kinase (AMPK), and adiponectin (ADIPOQ) gene in 1,070 patients with pancreatic cancer and 1,175 cancer-free controls that are enrolled in a case control study conducted at MD Anderson Cancer Center during 2000-2008. Information on risk factors was collected by personal interview. Genotypes were determined using the Taqman method. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated using multivariable unconditional logistic regression.

Results: The PPARγ P12A (rs1801282) GG genotype was inversely associated with risk of pancreatic cancer (AOR: 0.21, 95%CI: 0.07−0.62). Three NR5A2 variants (rs12029406, rs3790844 and rs3790843) that were previously identified in a genome-wide association study were significantly associated with reduced risk of pancreatic cancer, AORs ranging 0.57-0.79. Two FTO gene variants (rs8050136 and rs9939609) and one ADIPOQ variant (rs17366743) were differentially associated with pancreatic cancer according to levels of body mass index (BMI) (P interaction = 0.0001, 0.0015, and 0.03). The variant alleles were associated reduced risk of pancreatic cancer among individuals with normal weight but increased risk among those with excess body weight. For example, the AOR (95%CI) for FTO IVS1-2777 AC/AA genotype (rs8050136) was 0.72 (0.55-0.96) and 1.54 (1.14-2.09) in participants with a BMI <25 or ≥ 25 kg/m2, respectively. We observed no significant association between AMPK genotype and pancreatic cancer and no genotype interactions with diabetes or smoking.

Conclusion: Our findings suggest a protective effect of PPARγ P12A GG genotype and NR5A2 variants on pancreatic cancer. A positive association of FTO and ADIPOQ gene variants with pancreatic cancer may be limited to persons who are overweight.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3750. doi:10.1158/1538-7445.AM2011-3750
Abstract 3753: Genome wide association study of HCV-induced hepatocellular carcinoma
Authors: Matsuda Koichi , Kumar Vinod , Nakamura Yusuke
Published: June 2012

To identify the genetic susceptibility factor(s) for hepatitis C virus-induced hepatocellular carcinoma (HCV-induced HCC), a genome-wide association study (GWAS) was conducted using 432,703 autosomal SNPs in 721 HCV-induced HCC cases and 2,890 HCV-negative controls of Japanese origin. Eight SNPs which showed possible association (P < 1 × 10-5) in the GWAS were further genotyped in 673 cases and 2,596 controls. We found a novel locus in the 5 prime flanking region of HCRSP (hepatocellular carcinoma related soluble protein) gene (Pcombined = 4.21×10-13, odds ratio (OR) = 1.39) to be strongly associated with HCV-induced HCC. Subsequent analyses using patients with chronic hepatitis C (CHC) indicated that this SNP is not associated with CHC susceptibility (P = 0.61), but significantly associated with progression from CHC to HCC (P=3.13 × 10-8). We also found that risk allele of SNP was associated with lower level of HCRSP protein in HCV-induced HCC patients (P = 1.38 × 10-13). Thus, our results highlight the importance of genetic variations of HCRSP as a predictive biomarker for HCV-induced HCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3753. doi:10.1158/1538-7445.AM2011-3753
Abstract 376: Development of nanosuspension formulation of diethylstilbestrol and effect of particle size on the in vitro drug release
Authors: Samant Tanay , Tu Shi-Ming , Chow Diana S-L
Published: June 2012

Purpose: To develop a sustained release nanosuspension formulation of diethylstilbestrol (DES) for subcutaneous delivery, in recurrent prostate cancer, to by-pass the first pass hepatic metabolism and potentially reduce the adverse effects of DES.

Methods: Three nanosuspension formulations of DES were prepared by the wet milling technique with sizes of 160 (A), 300 (B) and 500 (C) nm, respectively. The formulations were characterized by particle size, zeta-potential and release kinetics. The release study was performed by adding each formulation, equivalent to 1mg of DES, to a dialysis bag (M.W cut off, 6000-8000). The bag was placed in 20 ml of PBS to simulate the subcutaneous conditions. The tubes were shaken at 100 rpm in a water bath at 37°C. The drug release was monitored for 14 days. DES concentrations were quantified by a validated HPLC assay.

Results: Sizes of the nanosuspensions were 162.5±1.5 nm, 287.1±2.7 nm and 492.5±8.3 nm, and the polydispersity was 0.18±0.01, 0.15±0.01, 0.20±0.03 for formulations A, B and C, respectively. The time of milling required for A, B and C was 30, 8 and 6 hours respectively. The zeta potential was -18.11±0.65, -19.49±0.49, -18.08±0.45 mV for formulations A, B and C, respectively. The release profiles showed a biphasic pattern, with an initial rapid release in 4 days followed by a slower release and reaching plateau after 6 days. Formulations A and B showed a significantly higher release than the formulation C by using ANOVA and Tukey's Multiple Comparison Test (p<0.05). However, there was no statistically significant difference between the release profiles of A and B. Formulation A had a much faster initial release rate of 25.06%/day than B and C with an initial release rate of 15.68%/day and 15.51%/day respectively (p<0.05). The extents of release were 65.76% (A), 67.38% (B) and 55.42% (C) at 6 days and 67.77% (A), 70.53% (B) and 64.79% (C) at 14 days.

Conclusion: Stable nanosuspension formulations were successfully formulated for DES with particle sizes of 162.5 nm, 287.1 nm and 492.5 nm. The particle size depends on the duration of milling. The 162.5 nm and 287.1 nm formulations achieved a much higher release than the 492.5 nm nanosuspension indicating that the particle size has a profound effect on the release of the drug. A sustained and extended release of DES was achieved over a period of 14 days in simulated subcutaneous conditions indicating that these formulations definitely warrant further preclinical evaluations.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 376. doi:10.1158/1538-7445.AM2011-376
Abstract 3770: tRNA-mediated regulation of nutrient-responsive pathways in breast cancer cell
Authors: Huynh Le-Nguyen , Neil Maria , Muthusamy Thangavel , Luu Hiep , Nair Devi , Ibba Mette P.
Published: June 2012

Autophagy or macroautophagy plays a crucial role in the survival of metabolic-stressed tumor cells by providing sufficient intracellular nutrients and energy to sustain growth. Cancer cells experiencing nutritional stress take advantage of the autophagic pathway to maintain viability. When cells experience nutritional stress, the activity of the serine/threonine kinase mTOR is downregulated, leading to reduced protein synthesis and subsequently increased autophagy. Under these conditions tRNAs, which are essential components of the protein synthesis machinery, accumulate in the nucleus. Cancer cells are often nutrient-starved, yet they still grow and proliferate, which indicates that sufficient amino acid-charged tRNAs are present in the cytosol to support protein synthesis. Our studies in human fibroblasts have shown that accumulation of tRNA in the nucleus, caused by reduced expression of the tRNA-transporting karyopherin Xpo-t, induces a starvation-like response, i.e. activity of the mTOR1C1 pathway is reduced and autophagy upregulated. Thus, we hypothesize that nuclear accumulation of tRNA signals cellular starvation.

In this work, we aim to determine if tRNA accumulation in the nucleus, accomplished by reduced expression of tRNA transporting karyopherin Xpo-t, induces a starvation response in breast cancer cells. Using MDA-MB-231 breast cancer cells as a model system for our in-vitro studies, we have shown significant response to nutrient starvation with regard to autophagy. We are currently analyzing if shRNA-mediated knockdown of Xpo-t in MDA-MB-231 cells triggers a starvation-response. Subsequently, we will determine if starvation in combination with Xpo-t knockdown lead to upregulation of autophagy and reduction of mTOR to such level that induces cancer cell death. Additional studies will be done to examine such response in other breast cancer cells and will be presented.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3770. doi:10.1158/1538-7445.AM2011-3770
Abstract 3771: Identification of novel small molecule inhibitors of the inducible heat shock protein Hsp70
Authors: Balaburski Gregor M. , Leu Julie , Hayik Seth A. , Andrake Mark , Dunbrack Roland , George Donna , Murphy Maureen E.
Published: June 2012

The stress induced molecular chaperone Hsp70 has a role in protein folding, assembly of multi-protein complexes and transport of proteins across membranes. Overall, this protein possesses significant cytoprotective and anti-apoptotic functions. High levels of Hsp70 can be found in many cancers, and these are associated with resistance to radiation and chemotherapy. Not surprisingly, overexpression of Hsp70 is generally a marker of poor patient prognosis. These combined data suggest that Hsp70, in addition to being a potential tumor prognostic marker, may also be a desirable molecular therapeutic target. 2-phenylethynesulfonamide (PES) was previously identified as a compound that inhibits apoptosis in thymocytes, by virtue of its ability to inhibit the direct p53 mitochondrial pathway. However, the mechanism of action of PES remained unknown. We recently demonstrated that PES specifically interacts with Hsp70, disrupts the interaction between Hsp70 and its co-chaperones and client proteins, and inhibits Hsp70 function at the lysosome. We further showed that PES exhibits selective toxicity to transformed cells by virtue of its ability to inhibit autophagy, a key survival pathway utilized by tumor cells. Here-in we report that we have used deletion mapping and molecular modeling to elucidate the domain of Hsp70 that interacts with PES. Additionally, to further elucidate the mechanism of action of PES, we generated and tested several analogues of PES. We find that the ability of PES to induce the death of tumor cells consistently correlates with its ability to inhibit autophagy. Further, we identified one analogue that has superior ability to induce programmed cell death in tumor cells. We are currently analyzing the efficacy and mechanism of action of this analogue in pre-clinical models.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3771. doi:10.1158/1538-7445.AM2011-3771
Abstract 3774: A novel drug discovery assay for analyzing autophagy in living cells
Authors: Shen Dee , Chan Eric , Pande Praveen , Coleman Jack , Patton Wayne F.
Published: June 2012

Autophagy is a normal degradative pathway that involves the sequestration of entire organelles, protein complexes, and misfolded proteins in a membrane vacuole called the autophagosome. The autophagosomal vesicle is subsequently delivered to the lysosome where it is degraded into its essential constituents and recycled back to the cytoplasm. Autophagy plays an important role in diverse biological events, not only during conditions of nutrient limitation, but it also functions in tumor suppression, the immune response, and the prevention of certain types of neurodegeneration. However, experimental methods to monitor this process in mammalian cells are limited due to lack of autophagic markers. Recently, LC3, a mammalian homologue of the ubiquitin-like (UBL) protein Atg8, has been used as a specific marker of autophagosomes in mammals. However, current methods to quantify autophagic activity using LC3 are time-consuming and labor-intensive. We have developed and validated a novel cell-based autophagy assay using a 488 nm-excitable green-emitting fluorescent probe to highlight the various vacuolar components of the autophagy pathway. We demonstrated that the accumulation of autophagy probe was specifically induced by amino acid deprivation and was inhibited by 3-methlyadenine, a classical inhibitor of the autophagic pathway. Furthermore, a population of this dye-labeled vesicle co-localizes with LC3. We have validated this fluorescent probe with a wide range of conditions known to modulate autophagy pathways. The assay is compatible with flow cytometry, allowing, for the first time, easy quantitation of autophagy. This assay enables kinetic analysis of the autophagy pathway and is able to distinguish between increases in autophagic flux vs. autophagic vacuole accumulation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3774. doi:10.1158/1538-7445.AM2011-3774
Abstract 3779: ARHI-induced autophagy is mediated through activation of FoxO3a and induction of its target genes to promote the formation of autophagic complexes
Authors: Liao Warren S. , Lu Zhen , Gao Fengqin , Yang Maojie , Bast Robert C.
Published: June 2012

The role of autophagy in oncogenesis remains ambiguous and the mechanisms that induce autophagy and regulate its outcome in human cancer are poorly understood. ARHI (DIRAS3), a Ras-related tumor suppressor, is downregulated in >60% of ovarian cancers. Re-expression of ARHI in ovarian cancer cells induces autophagy in culture and in xenografts, by blocking Ras activation and inhibiting PI3 kinase activity. ARHI also participates directly in the formation of autophagosomes by upregulating Atg4 and co-localizing with processed LC-3 II. Here we show that inhibition of PI3 kinase/Akt signaling and Ras activation by ARHI is mediated, in part, by down regulation of EGFR expression and EGFR phosphorylation. Inhibition of these signaling pathways reduced phosphorylation of FoxO3a and enhanced nuclear accumulation of FoxO3a transcription factor, resulting in increased transcription of Atg4, MAP-LC-3, and PUMA. Knockdown of FoxO3a by siRNA reduced ARHI- and rapamycin-induced autophagy. Whereas ARHI inhibits Class I PI3K activity, its expression induces Class III PI3K activity and contributes to the enhanced autophagy. Thus, ARHI-induced autophagy is through activation of the transcription factor FoxO3a, which increases the expression of several autophagy-related genes that contribute to the formation of the autophagic complexes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3779. doi:10.1158/1538-7445.AM2011-3779
Abstract 3784: HMGB1 affects plasma amino acid profiles in colon carcinogenesis
Authors: Kuniyasu Hiroki , Luo Yi , Ohmori Hitoshi , Fujii Kiyomu , Sasahira Tomonori , Chihara Yoshitomo , Yoneda Junya , Shimbo Kazutaka , Eto Sachise
Published: June 2012

Alteration of the plasma free amino acid profile was reported to be a potential marker of colorectal cancer and breast cancer. The plasma amino acid profile has been reported as a relevant marker for early detection of colorectal cancer (Okamoto N et al. Int J Med Med Sci, 2009). In the present study, we examined the plasma amino acid profile as a marker for evaluating colon cancer risk. The amino acid profiles were examined in the mouse plasma using DMH-induced C57BL6 mouse colon carcinogenesis model. The plasma amino acid profiles of DMH-treated mice were different from that in control mice. Importantly, the plasma amino acid profile at procarcinogenic phase was also distinguished from the control. We focused on HMGB1, which was timely increased in serum and colon mucosa of the DMH-treated mice. In HMGB1-adeministrated mice, the plasma amino acid profiles showed a resemble pattern with that in the procarcinogenic phase mice. Decrease of most amino acids in the liver and skeletal muscle suggested an increase of catabolism in HMGB1-treated mice. In the mouse liver and muscle tissues, HMGB1 decreased pyruvate kinase M1 expression, and tetrazolium desoxydation, whereas lactate production was not increased. HMGB1 decreased phosphorylation levels of mTOR and increased protein levels of Beclin1 and LC3 in mouse liver and muscle tissue, whereas a mitochondrial marker, Diablo was not affected. Inhibitor of p38 MAPK abrogated HMGB1-induced autophagy signals. These findings suggest that HMGB1 affects energy production in mitochondria and activates autophagy signals, which might induce protein degradation and subsequent alteration of plasma amino acid profiles. The change of the plasma amino acid profiles might be a key finding detecting procarcinogenic status of the colon.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3784. doi:10.1158/1538-7445.AM2011-3784
Abstract 3794: BAX maintains mitochondrial bioenergetics in colon cancer cells
Authors: Boohaker Rebecca J. , Zhang Ge , Carlson Adina L. , Nemec Kathleen N. , Khaled Annette R.
Published: June 2012

The dual functionality of the tumor suppressor, BAX, is implied by the non-apoptotic functions of other pro-apoptotic BCL-2 family proteins. To explore this, the mitochondrial morphology and ATP producing capability in both BAX-containing and BAX-deficient HCT-116 colon cancer cells were examined. While BAX deficient cells maintain the same mitochondrial mass as their BAX containing counterparts, these mitochondria were visibly smaller, more compact, and unable to maintain an organized network. Oxygen consumption and ATP levels were also reduced in these cells, a phenomenon that was replicated upon treatment of BAX-containing cells with the uncoupling agent, FCCP. These results, coupled with a marked decrease in citrate synthase activity, suggested that cells lacking BAX have a deficiency in the ability to generate ATP through oxidative phosphorylation. Inhibition of endogenous BAX through treatment with small interfering RNAs reinforced the necessity of BAX activity in the maintenance of aerobic respiration and the production of ATP. An examination of the localization of full length and C-terminal truncated BAX in non-apoptotic, BAX deficient cells, indicated that a small fraction of the existing cytosolic BAX is needed at the mitochondrial membrane to maintain ATP production. However, this function is not dependent upon the C-terminal helix. Co-expression of BAX and BCL-2 resulted in a subsequent loss of ATP production, implying that, even under non-apoptotic conditions, an antagonistic interaction exists between the two proteins. These findings infer that a basal amount of BAX associated with the mitochondria is necessary to maintain mitochondrial bioenergetics. The discovery of this novel, non-apoptotic role for BAX in the maintenance of ATP synthesis and suggests that complete abrogation of BAX would be detrimental to cancer cells dependent on energy production via aerobic respiration.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3794. doi:10.1158/1538-7445.AM2011-3794
Abstract 3803: Potential role of multidrug resistance associated protein (MRPs) in hypoxia-induced drug resistance of non-small cell lung cancer cells (H460)
Authors: Chen Yu-Lun , Chang Chia-Lun , Lin Li-Chiung , Hsueh Chi-Mei
Published: June 2012

H460 is a non-small cell lung cancer (NSCLC) cell with multidrug resistance (MDR) against a variety of anti-cancer drugs such as cisplatin and transforming growth factor-beta (TGF-beta). It has been reported that hypoxia can trigger the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and the subsequent production of P-glycoprotein (P-gp, the archetype of MDR associated proteins or MRPs) that eventually lead to chemotherapeutic resistance of various cancer cell lines as well as NSCLC patients. The primary concern of this study was to know would hypoxia promote drug resistance of H460 cells via MRPs (MRP1 and MRP3). The experimental strategies applied were to evaluate the hypoxic impacts upon: 1) the drug resistance of H460 cells against doxorubicin (DOX, a commonly used chemotherapeutic drug in many cancer treatments), using MTT assay; 2) the expression of MRP1, MRP3 and HIF-1alpha of H460 cells in the absence or presence of DOX, using Western blot analysis; 3) the intracellular accumulation of DOX in H460 cells, using flow cytometry. The current results showed that DOX triggered a dose- and time-dependent cell death of H460. A hypoxia-induced DOX resistance was observed in H460 cells. Western blot analysis further showed that DOX-decreased MRP1 was further exacerbated under hypoxic condition that precluded the possible involvement of MRP1 in hypoxia-induced drug resistance. DOX on contrary increased the expression of MRP3. The potential contribution of MRP3 to hypoxia-induced DOX resistance and its role in pumping out of DOX from H460 cells are currently investigated in our laboratory. Finally, hypoxia-induced HIF-1alpha remained still high in the presence of DOX, suggesting a potential role of HIF-1alpha in promoting the DOX resistance of H460. Results from the study can uncover the molecular mechanisms underneath hypoxia-induced DOX resistance of H460 that consequently can lead to therapeutic target(s) for treatment of NSCLC cells (H460).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3803. doi:10.1158/1538-7445.AM2011-3803
Abstract 3809: TMPRSS2-ERG gene fusion is strongly associated with elevated androgen receptor expression in early prostate cancer
Authors: Minner Sarah Jane Pauline , Sirma Hueseyin , Simon Ronald , Krohn Antje , Burandt Eike , Tennstedt Pierre , Becker Michael , Schlueter Hartmut , Graefen Markus , Huland Hartwig , Schlomm Thorsten , Sauter Guido
Published: June 2012

Introduction and Objective: About 50% of prostate cancers have TMPRSS2-ERG fusions resulting in ERG overexpression. The aim of this study was to determine whether prostate cancer of “fusion-type” differs from “non-fusion” prostate cancer both clinically and molecularly.

Methods: A prostate cancer tissue microarray (TMA) consisting of over 2,500 cancer samples was analyzed for ERG protein expression and TMPRSS2-ERG gene fusion by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Results were compared with tumor phenotype, clinical outcome, and molecular features previously determined in studies using the same TMA. Furthermore, a fresh frozen prostate cancer TMA containing 41 “fusion-type” and 21 “non-fusion” prostate cancers was analyzed by MALDI (Matrix Assisted Laser Desorption/Ionisation) mass spectrometric imaging, a technology analyzing proteomic patterns directly on tissue sections. Functional analyses included comparisons of androgen receptor (AR) mRNA levels in LNCaP cells before and after induced ectopic ERG overexpression through lentiviral vectors.

Results: Detectable ERG protein expression was found in 52% of 2818 interpretable cancers on our TMA and TMPRSS2-ERG fusion was observed by FISH in 42% of 947 interpretable cases. The data did not reveal any clinical or prognostic significance of ERG protein expression and TMPRSS2-ERG fusion. However, several molecular features differed between “”fusion-type” and “non-fusion” prostate cancers, including AR, AMACR, Annexin A3, Bcl2, CD10, CD166, Chromogranin A, EGFR, HER2 and mTOR. The strongest difference was found for AR expression, which was considered strong in 62.9% of ERG negative but in 81.0% of ERG positive cancers. In the LNCaP cell line, ectopic ERG overexpression lead to a marked downregulation of androgen receptor dependent transcription. MALDI imaging identified several additional masses that differed significantly between “fusion-type” and “non-fusion” tumors.

Conclusions: There is no particular clinical behavior of “fusion-type” and “non-fusion” cancers in surgically treated patients. The TMPRSS2-ERG fusion determines a distinct subgroup of prostate cancers, which strongly differ on the molecular level as detected by immunohistochemistry and MALDI imaging. Furthermore, our data indicate that ERG modulates the transcription of AR-dependent genes in prostate cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3809. doi:10.1158/1538-7445.AM2011-3809
Abstract 3817: Chromosome specific telomeres and breast cancer risk
Authors: Zheng Yun-Ling , Zhou Xin , Loffredo Christopher A. , Shields Peter G. , Sun Bing
Published: June 2012

Although telomere dysfunction is a characteristic of breast cancer cells, the relationship between deficiency on individual chromosomal telomeres in normal somatic cells and breast cancer risk has not been characterized. A case-control study was conducted to examine the associations between individual lengths of 92 telomeres in the human genome and the risk of breast cancer in 204 newly diagnosed breast cancer patients and 236 healthy controls. Chromosome arm-specific telomere lengths were measured by telomere quantitative fluorescent in situ hybridization (TQ-FISH). Unconditional logistic regression was used to estimate the risk associations. This genome-wide screen identified that shorter telomere lengths on chromosome Xp and 15p were associated with breast cancer risk in premenopausal women, with adjusted odds ratios (aOR) of 2.5 (95% CI = 1.3, 4.8), and 2.6 (1.3, 5.0), respectively. The study also revealed that greater length differences between homologous telomeres on chromosome 9p, 15p and 15q were associated with breast cancer risk in premenopausal women, with aORs of 4.6 (2.3, 9.2), 3.1 (1.6, 6.0), and 2.8 (1.4, 5.4) respectively. When the subjects were categorized into quartiles, a dose response relationship was observed for all of the above telomeres (P-for-trend < 0.005). This study revealed that telomere deficiencies on chromosome 9p, 15p, 15q and Xp were associated with breast cancer risk in premenopausal women. If confirmed in future studies, chromosomal arm-specific telomeres are likely to be a useful panel of blood-based biomarkers for breast cancer risk assessment, given their strong associations with breast cancer risk.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3817. doi:10.1158/1538-7445.AM2011-3817
Abstract 3820: Deregulation of KEAP1-NRF axis in phenotypically type 2 papillary renal cell carcinoma
Authors: Ooi Aikseng , HM Bernice Wong , Wong JingChii , Perrier-Trudova Victoria , Petillo David , Roossien Douglas , Zhang Zhongfa , Tan Min-Han , Zhou Ming , Yang Ximing , Richard Stéphane , Teh Bin Tean , Furge Kyle A.
Published: June 2012

Type 2 papillary renal cell carcinoma (PRCC2) is an aggressive subtype of kidney cancer that has no known effective treatment modality. The hereditary form of the tumor is known to associate with the loss of fumarate hydratase (FH) gene function. However, FH gene mutation has yet to be found in sporadic PRCC2. Herein, we report the overexpression of antioxidant response element (ARE) controlled genes as a common feature that is shared between the hereditary and sporadic form of PRCC2. We demonstrate that fumarate stabilizes NRF1 and NRF2, which drive the upregulation of ARE controlled genes. We propose that fumarate stabilizes NRF1 and NRF2 through direct suppression of KEAP1. This finding better explains the phenotypical differences that are apparent between PRCC2 and CCRCC and may lead to the development of an effective therapeutic against PRCC2.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3820. doi:10.1158/1538-7445.AM2011-3820
Abstract 3825: Prognosis of esophageal adenocarcinoma is dependent on early G1 cyclin-dependent kinase activity
Authors: Ismail Amin , Bandla Santhoshi , Toia Liana , Zhou Zhongren , Gooding William E. , Reveiller Marie , Kalatskaya Irina , Stein Lincoln , D'Souza Mary , Litle Virginia R. , Peters Jeffrey H. , Pennathur Arjun , Lucketich James D. , Godfrey Tony E.
Published: June 2012

Background: Chromosomal gain at 7q21 is a frequent event in esophageal adenocarcinoma (EAC). However, this event has not been mapped with fine resolution in a large EAC cohort and its associations with clinical endpoints and functional relevance are unclear.

Methods: We used a cohort of 116 patients to fine map the 7q21 amplification using SNP microarrays. 7q21 amplification and its gene expression were explored for associations with patient survival. Effects of siRNA-mediated knockdown of CDK6, its homolog CDK4 and the CDK4/6 inhibitor PD-0332991 were studied in vitro.

Results: 34.5% of tumors harbor 7q21 amplification which spans 17 genes with a focal amplicon of 6 genes. The amplification is associated with patient overall survival. Correlation of gene expression and survival identified CDK6 as the only gene in the core amplicon whose expression strongly associates with poor survival. In addition, the expression of CDK4, which is an unamplified homolog of CDK6, correlates with poor survival. The combined expression of both genes is a superior predictor of survival than either alone. siRNA-mediated knockdown of CDK4 and/or CDK6 suggests that they are required for proliferation of EAC cells and that their function is additive. PD-0332991 targets the kinase activity of both molecules and suppresses proliferation and anchorage-independence of EAC cells through activation of the pRB tumor suppressor pathway.

Conclusion: We refined 7q21 amplification in EAC and demonstrate its association with poor survival. We suggest that CDK6 is the driver of the amplicon and that prognosis of EAC is dependent on its expression along with its homolog CDK4. Targeting these molecules may thus constitute a viable new therapy for EAC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3825. doi:10.1158/1538-7445.AM2011-3825
Abstract 3828: RDEA119 synergy the anti-tumor effect of sorafenib in renal cell carcinoma cells
Authors: Kim Mi Joung , Hwang Jung Jin , Choi Jene , Lee Sang-wook , Kim Choung-Soo
Published: June 2012

The MEK signaling pathway is over-expressed in more than 30 percentages of cancers, leading to cell growth and proliferation. Renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) is a particularly vascularized solid tumor where the Raf/MEK/ERK pathway is activated; suggesting that inhibition of this pathway may have therapeutic targets. Sorafenib as a multi-kinase inhibitor against Raf, VEGFR-2, PDGFR, c-kit, and FLT3 approved by the FDA for treatment of advanced renal cell and hepatocellular carcinomas. Since it was reported recently that combination treatment with sorafenib and MEKI exerted synergistic effect on cell proliferation in HCC, we studied the anti-proliferative effect of RDEA119 as a single agent or in combination with sorafenib for the treatment of RCC and HCC. We examined cell death effect on cell viability in 8 kinds of RCC cells and 6 kinds HCC cells. Treatment with RDEA119 inhibited proliferation of TK-10, UO31, A497 (RCC) and HepG2 (HCC) cells.

In the case of combination treatment, pre-treatment with RDEA119 potentiated anti-proliferative effect of sorafenib in A498 cells (ccRCC and VHL-/-). This combination showed synergism in combination index and isobolograms analyzed by CalcuSyn software. Furthermore, the combination treatment activated caspases-3, -9 and -8, which resulted in intrinsic and extrinsic apoptosis. To figure out cell death mechanism activated by this combination, we analyzed the phosphorylation of phospho-ERK (p-ERK) and p-AKT in A498 cells. Single treatment with RDEA119 decreased p-ERK effectively, but increased p-AKT. On the other hand, sorafenib alone decreased p-AKT, but increased p-ERK. However, combination treatment with RDEA119 and sorafenib inhibited phosphorylation of MEK and AKT completely. The combination treatment decreased the level of p-GSK3β and anti-apoptotic protein, MCL-1 which are related to survival. Our study indicates that MEK inhibitor (MEKI) alone suppressed cell proliferation and the combination of MEKI with sorafenib increased apoptosis synergistically by decreasing activation of AKT pathway as well as ERK pathway in A498 cells. These results suggest that it may be a new therapeutic modality for treatment of ccRCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3828. doi:10.1158/1538-7445.AM2011-3828
Abstract 3836: Identification of PTPsigma as an autophagic phosphatase
Authors: Martin Katie R. , Xu Yong , Looyenga Brendan D. , Davis Ryan J. , Wu Chia-Lun , Tremblay Michel L. , Xu H Eric , Mackeigan Jeffrey P.
Published: June 2012

Macroautophagy is a dynamic process whereby portions of the cytosol are encapsulated in double-membrane vesicles and delivered to the lysosome for degradation. Phosphatidylinositol-3-phosphate (PI(3)P) is concentrated on autophagic vesicles and recruits effector proteins critical for this process. The production of PI(3)P by the class III phosphatidylinositol 3-kinase (PI3K), Vps34, has been well established; however, protein phosphatases which antagonize this early step in autophagy remain to be identified. To identify such enzymes, we screened human phosphatase genes by RNA interference (RNAi) and found that loss of PTPsigma, a dual-domain protein tyrosine phosphatase (PTP), increases cellular PI(3)P. The abundant PI(3)P-positive vesicles conferred by PTPsigma loss strikingly phenocopied those observed in amino acid-starved cells. Accordingly, we discovered that loss of PTPsigma hyperactivates both constitutive and induced autophagy. Finally, we found that PTPsigma localizes to PI(3)P-positive membranes in cells and this vesicular localization is enhanced during autophagy. Our findings propose a novel role for PTPsigma and provide insight into the regulation of autophagy. Mechanistic knowledge of this process is critical for understanding and targeting therapies for several human diseases, including cancer and Alzheimer's disease, in which abnormal autophagy may be pathological.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3836. doi:10.1158/1538-7445.AM2011-3836
Abstract 3837: Protein Phosphatase PHLPP regulates protein translation and cell size through directly dephosphorylating p70 S6 kinase
Authors: Liu Jianyu , Stevens Payton , Gao Tianyan
Published: June 2012

PHLPP (PH domain Leucine rich repeats Proten Phosphatase) is a family of Serine/Threonine protein phosphatases that has been identified to dephosphorylate Akt and PKC. We have shown previously that PHLPP functions as a tumor suppressor by negatively regulating Akt signaling in cancer cells. Here we report the identification of p70 S6 kinase (p70S6K) as a novel substrate of PHLPP. Purified PP2C domain of PHLPP specifically dephosphorylated p70S6K at Thr389 site in vitro and reduced its kinase activity towards purified S6 ribosomal protein. The interaction between PHLPP and p70S6K was detected by co-immunoprecipitation. Overexpression of both PHLPP isoforms resulted in a decrease in p70S6K phosphorylation. Furthermore, this PHLPP-mediated dephosphorylation of p70S6K was independent of its effect on Akt signaling, as PHLPP was capable to dephosphorylate p70S6K in Rictor knockout MEF cells. Interestingly, knockdown of PHLPP in 293E and certain colon cancer cells resulted in an increase in p70S6K phosphorylation and a decrease in Akt activity. Consistent with activation of a negative feedback loop via the p70S6K-IRS1-PI3K axis, we showed that IRS1 expression was significantly decreased in the PHLPP knockdown cells. Treating cells with Rapmycin, an mTOR inhibitor, to release the negative feedback regulation, the phosphorylation of Akt was restored more readily in the PHLPP knockdown cells compared to the control cells. Similarly, the phosphorylation of p70S6K induced by insulin was elevated whereas Akt activation was suppressed in PHLPP1 knockout MEF cells. Functionally, the amount of p70S6K bound to translation initiation factor eIF3 was decreased, whereas the amount of phosphorylated S6 ribosomal protein in the initiation complex bound to the cap structure was increased in PHLPP knockdown cells. This correlates with increased cap dependent translation as measured by a luciferase reporter assay. Moreover, the cell size and protein contents were increased in PHLPP knockdown and knockout MEF cells. Taken together, our results demonstrate that loss of PHLPP expression may activate p70S6K-dependent negative feedback loop, and PHLPP is a novel player involved in regulating protein translation initiation and cell size via direct dephosphorylation of p70S6K.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3837. doi:10.1158/1538-7445.AM2011-3837