bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2540: Survival after cutaneous melanoma in kidney transplant recipients: a population-based matched cohort study.
Authors: Vajdic Claire M. , Chong Alvin H. , Kelly Patrick J. , Meagher Nicola S. , van Leeuwen Marina T. , Grulich Andrew E. , Webster Angela C.
Published: August 2014

BACKGROUND

Early detection and tailored treatment algorithms have resulted in improved outcomes for patients with cutaneous melanoma. Solid organ transplant recipients are at elevated risk of melanoma, and may have poorer outcomes than non-transplant recipients, although the evidence is unreliable.

METHODS

We conducted a national, population-based, matched cohort study of de novo invasive cutaneous melanoma in Australian kidney transplant recipients and in randomly selected members of the general population matched for age, sex, state of residence, and year of diagnosis (1982-2003). Melanoma histopathological characteristics were extracted from cancer registry notifications and date of death was obtained by linkage with the National Death Index (1982-2011). Kaplan Meier curves and Cox proportional hazard models were used to analyse the overall survival of transplant and non-transplant recipients, adjusted for matching and histopathological characteristics.

RESULTS

Compared to non-transplant recipients (n=202), melanomas in transplant recipients (n=75) were more likely to have a higher AJCC pathologic stage (P=0.003) at diagnosis. Survival was significantly lower for recipients compared to non-recipients, overall and for stage I melanomas (P<0.001). Transplantation was associated with a significantly increased risk of death (adjusted hazards ratio 8.06; 95% confidence interval, 3.92 to 16.6, P<0.0001). Pathologic stage (P=0.0004) and histology (P=0.009) also independently predicted risk of death.

CONCLUSIONS

Transplant recipients have a markedly poorer outcome than non-recipients after melanoma diagnosis. A review of patient education and skin cancer screening guidelines is warranted. Treatment algorithms developed for the general population with melanoma do not appear to apply to transplant recipients.

Citation Format: Claire M. Vajdic, Alvin H. Chong, Patrick J. Kelly, Nicola S. Meagher, Marina T. van Leeuwen, Andrew E. Grulich, Angela C. Webster. Survival after cutaneous melanoma in kidney transplant recipients: a population-based matched cohort study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2540. doi:10.1158/1538-7445.AM2013-2540
Abstract 2543: A genome-wide analysis of ROHs identifies two susceptibility regions for non-cardia gastric cancer in han Chinese.
Authors: Hu Zhibin , Wang Cheng , Jin Guangfu , Lin Dongxin , Shen Hongbing
Published: August 2014

Runs of homozygosity (ROHs) are a novel class of genomic variation and may involve in the individual susceptibility to diseases. To better understand ROH and its relationship with non-cardia gastric cancer, we performed a genome-wide ROH analysis in two independent case-control studies (Nanjing study: 565 cases and 1,162 controls; and Beijing study: 468 cases and 1,123 controls) from Han Chinese populations. ROHs with a length from 0.5 to 1.5 Mb defined by at least 50 single nucleotide polymorphisms (SNPs) were evaluated with the association of non-cardia gastric cancer risk using genome-wide SNP data. We found that the overall ROH levels were significantly associated with a decreased risk of non-cardia gastric cancer risk (odds ratio (OR) =0.60; 95% confidence interval (CI): 0.50-0.73; P = 2.95×10-7). We also identified two ROHs at 15q13.2 and 2q14.2 that were consistently associated with non-cardia gastric cancer risk in both the Nanjing study (15q13.2: OR=0.55; and 2q14.2: OR=1.69) and the Beijing study (15q13.2: OR=0.41; and 2q14.2: OR=1.67). After combining the two studies, the association reached genome-wide significance level (9,749 ROHs, P<5×10-6) for 15q13.2 (OR=0.51, 95%CI: 0.38-0.67, P=2.49×10-6) but not 2q14.2 (OR=1.68, 95%CI: 1.30-2.18, P=9.06×10-5). These results suggest that overall ROH levels may play a protective effect against non-cardia gastric cancer, and 15q13.2 and 2q14.2 regions may be new susceptibility loci for non-cardia gastric cancer.

Citation Format: Zhibin Hu, Cheng Wang, Guangfu Jin, Dongxin Lin, Hongbing Shen. A genome-wide analysis of ROHs identifies two susceptibility regions for non-cardia gastric cancer in han Chinese. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2543. doi:10.1158/1538-7445.AM2013-2543
Abstract 2547: Targeted sequencing of 5p15 locus defined by non-small cell lung cancer (NSCLC) GWAS using next-generation sequencing.
Authors: Wang Zhaoxi , Zhao Yang , Su Li , Lee Seunggeun , Lin Xihong , Christiani David C.
Published: August 2014

Recent genome-wide association studies (GWAS) have identified genetic loci associated with lung cancer risk. Direct sequencing is regarded as the ultimate approach for moving beyond genetic mapping to identify causal mutations and define disease candidate genes. We conducted a pilot next-generation sequencing (NGS) of all exons of TERT and CLPTM1L genes within the 5p15 locus from our NSCLC GWAS, replicating previous studies. We performed an amplicon capture-NGS on 138 samples, including 82 NSCLC cases and 56 controls. These results were highly consistent across samples, with the majority covering 85-95% of bases at 100-fold and with only 5 samples failing to achieve 100-fold coverage for at least 80% of bases. We identified 11 SNPs in TERT and 5 SNPs in CLPTM1L. Using our SKAT/SKAT-O method, we found that both genes were associated with NSCLC (TERT, p=0.006; and CLPTM1L, p=0.04). When the SNPs of the two genes were combined, we saw a greater joint effect (p=0.001). In a subgroup analysis focusing on functional SNPs, including 7 and 4 nonsynonymous SNPs in TERT and CLPTM1L, respectively, we found a stronger association with TERT (p=0.0005), as well as an increased joint effect (p=0.0001). Moreover, none of the sequenced subjects had functional SNPs in both TERT and CLPTM1L genes. Furthermore, most nonsynonymous variations seemed clustered either in the cases or in the controls. Bioinformatic annotation of these nonsynonymous SNPs revealed that those clustered in the controls had only benign effects on the encoded protein, whereas those overrepresented in the NSCLC cases had possible damage to the encoded protein. Using Sanger dideoxy-terminator sequencing at an independent core facility and Taqman genotyping, all of the 11 functional SNPs identified by amplicon capture-NGS were confirmed. In summary, the results seem to support the hypotheses that aggregated functional variations, but not the neutral ones, contribute to the risks of NSCLC development. However, the initial finding is not conclusive, as this pilot project was limited by a small sample set and structural variations were not examined.

Citation Format: Zhaoxi Wang, Yang Zhao, Li Su, Seunggeun Lee, Xihong Lin, David C. Christiani. Targeted sequencing of 5p15 locus defined by non-small cell lung cancer (NSCLC) GWAS using next-generation sequencing. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2547. doi:10.1158/1538-7445.AM2013-2547
Abstract 2560: MicroRNA target site polymorphisms and colorectal cancer risk in the Ashkenazi Jewish population.
Authors: Stenzel Stephanie L. , Gollub Jeremy , Shapero Michael , Finn Andrea , Rennert Gad , Gruber Stephen B.
Published: August 2014

MicroRNAs (miRNAs) act as key post-transcriptional regulators of gene expression via binding to the 3’ untranslated regions (UTRs) of mRNAs. Single nucleotide polymorphisms (SNPs) found in the miRNA sequence and/or corresponding binding sites can affect the fidelity of this interaction, and evidence from candidate miRNA studies suggests that such SNPs may increase or decrease risk of tumor development. This study was designed to expand the search for miRNA-related polymorphisms important in cancer etiology across the genome and to investigate the association between thousands of genetic variants in miRNA target sites and colorectal cancer (CRC) risk using a novel genotyping platform, the Axiom® miRNA Target Site Genotyping Array (237,858 markers). The final study sample after quality control filtering included 605 cases and 615 controls from the Molecular Epidemiology of Colorectal Cancer (MECC) study, a population-based case-control study of incident CRC cases in a geographically-defined area of northern Israel. The marginal association between each marker with minor allele frequency >=1% and CRC risk was examined assuming a log-additive genetic model using logistic regression adjusted for sex, age, and the first two principal components (PC) to capture fine-scale population structure. There were 11 markers with p-values less than 3E-4, and the most statistically significant association involved rs12130051 (chr1:19545053; 3’-UTR of KIAA0090) with an OR of 2.24 (1.52,3.31) and p=4.48E-5. In addition, rs1051690 (chr5:142605172; 3’-UTR of ARHGAP26), was statistically significantly associated with decreased CRC risk (OR (95% CI): 0.71 (0.59, 0.85); p = 2.03E-4). Further, this study provided evidence for replication of a previously published locus, rs1051690 in the 3’UTR region of the insulin receptor gene, INSR (OR (95% CI): 1.27 (0.96,1.67); p = 0.09). A fixed-effects meta-analysis of sample-size weighted p-values from a recent publication in Carcinogenesis describing the INSR variant (Landi et al., 2012) and from the current MECC study yielded a combined p-value of 0.01. To our knowledge, this is the first study to examine the association between genetic variation in miRNA target sites and cancer risk using a genome-wide approach. Work is ongoing to replicate findings from this study and to characterize the functional impact of prioritized polymorphisms.

Citation Format: Stephanie L. Stenzel, Jeremy Gollub, Michael Shapero, Andrea Finn, Gad Rennert, Stephen B. Gruber. MicroRNA target site polymorphisms and colorectal cancer risk in the Ashkenazi Jewish population. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2560. doi:10.1158/1538-7445.AM2013-2560
Abstract 2571: Genetic variations in telomere maintenance pathway genes are associated with risk of esophageal cancer.
Authors: Ye Yuanqing , Ajani Jaffer , Wu Xifeng
Published: August 2014

Many studies have shown the association of telomere dysfunction with aging and cancer development. We hypothesize that genetic variations in telomere maintenance genes may modulate esophageal cancer risk. To test this hypothesis, we comprehensively assessed the association of 616 SNPs in 45 telomere maintenance pathway genes in 602 esophageal adenocarcinoma cases and 1,512 healthy controls. Unconditional multivariate logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) while adjusting for age, gender, and smoking status. In single SNP analysis, a total of 77 SNPs had P value < 0.05. 5 SNPs remained significant after adjusting for multiple comparisons at FDR < 0.10 including 3 SNPs in PINX1 gene and 2 SNPs in TPP1 gene. The most significant association was observed for rs9657541 in PINX1 gene that exhibited a significantly reduced risk of esophageal cancer in dominant model (OR = 0.62, 95% CI = 0.50-0.77, P = 1.54×10−5, FDR = 0.020). Cumulative effects of SNPs were assessed by the number of unfavorable genotypes. Each subject was classified into low (zero unfavorable genotype), medium (one to three unfavorable genotypes), and high-risk groups (more than three unfavorable genotypes). Compared with the low-risk group, the OR was 1.58 (95% CI = 1.20-2.09) for the median-risk group and 2.57 (95% CI = 1.87-3.54) for the high-risk group. Classification and regression tree (CART) analysis was performed to identify genetic profiles that can classify individuals into differential risk of esophageal cancer. CART analysis identified 3 terminal nodes. Compared to terminal node 1, individuals in terminal nodes 2 and 3 had significantly increased risks of esophageal cancer with ORs of 1.43 (95% CI = 1.13-1.80) and 2.46 (95% CI = 1.81-3.34), respectively. We also performed gene-based analysis to determine the combined effect of SNPs within a gene region and identified four genes (TPP1, PINX1, TNKS, TERF1) significantly associated with the risk of esophageal cancer. In conclusion, our results suggest that genetic variants in telomere maintenance pathway genes may contribute to the altered risk of esophageal cancer, both individually and jointly.

Citation Format: Yuanqing Ye, Jaffer Ajani, Xifeng Wu. Genetic variations in telomere maintenance pathway genes are associated with risk of esophageal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2571. doi:10.1158/1538-7445.AM2013-2571
Abstract 2572: Vitamin D intake and lung cancer risk in the Women's Health Initiative (WHI).
Authors: Cheng Ting-Yuan David , LaCroix Andrea Z. , Beresford Shirley A.A. , Goodman Gary E. , Thornquist Mark D. , Zheng Yingye , Chlebowski Rowan T. , Ho Gloria Y.F. , Neuhouser Marian L.
Published: August 2014

Background: Prior research suggests that vitamin D protects against lung cancer with evidence only among subgroups including women and non-smokers. We investigated whether vitamin D intake was associated with lung cancer and explored whether vitamin A intake modified the association.

Methods: Data from 128,779 postmenopausal women including 1,771 incident lung cancers in the Women's Health Initiative, 1993-2010, were analyzed. Twelve percent of women received active intervention (1 g calcium+400 IU vitamin D3 daily) in the Calcium/Vitamin D Trial. Baseline total intake was assessed by a food frequency questionnaire and supplement bottle labels. Hazard ratios (HR) were estimated by Cox proportional hazard models.

Results: No association was observed overall. Among never smokers, vitamin D intake was inversely associated with total lung cancer (HR=0.37, 95% confidence interval [CI]=0.18-0.77, ≥800 vs. <100 IU/d; P-trend=0.01). The Calcium/Vitamin D Trial active intervention was not associated with a lower lung cancer risk among women with vitamin A intake ≥1,000 μg/d Retinol Activity Equivalent (RAE), but among those with vitamin A intake <1,000 μg/d RAE (HR=0.69, 95% CI=0.50-0.96; P-interaction=0.09). Among current smokers with excess vitamin A intake (≥3,000 μg/d RAE), the intervention was associated with a higher lung cancer risk (HR=2.26, 95% CI=1.02-5.01), as no association was observed among current smokers with vitamin A intake <3,000 μg/d RAE (P-interaction=0.01).

Conclusion: Vitamin D intake was associated with a lower lung cancer risk in never-smoking, postmenopausal women. Lower vitamin A intake may be important for a beneficial association of 1 g calcium+400 IU vitamin D3 supplementation with lung cancer.

Citation Format: Ting-Yuan David Cheng, Andrea Z. LaCroix, Shirley A.A. Beresford, Gary E. Goodman, Mark D. Thornquist, Yingye Zheng, Rowan T. Chlebowski, Gloria Y.F. Ho, Marian L. Neuhouser. Vitamin D intake and lung cancer risk in the Women's Health Initiative (WHI). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2572. doi:10.1158/1538-7445.AM2013-2572
Abstract 2573: Serum proteomic analysis of early pregnancy-induced protection against breast cancer.
Authors: Gutierrez Christina , Arumugam Arunkumar , Lopez Rebecca , Boopalan Thiyagarajan , Nandy Sushmita , Agullo Pamela , Parada Jacqueline , Love Susan , Lakshmanaswamy Rajkumar
Published: August 2014

The incidence of breast cancer is very high in western countries and is increasing rapidly in the third world. It is the most common cancer in women worldwide. Since it is difficult to defeat breast cancer after it has occurred, finding new strategies to delay or prevent the development of breast cancer has been an important area for clinical and experimental investigations. Women who undergo a full- term pregnancy before the age of 20, with or without lactation, have about one half the risk of developing breast cancer compared to women who undergo their first pregnancy after the age of 35 or women who have never undergone a full term pregnancy. This universal protective effect of pregnancy serves as a major clue and starting point in the search for new strategies and novel biomarkers related to the prevention of breast cancer. For the current study, women were recruited into one of the following categories; 1) had their first child ≤ 25 years of age [early parous], 2) had their first child ≥ 35 years of age [late parous], and 3) a control group of women the same age as those in groups 1 and 2 but who have never given birth [nulli parous]. Blood was collected these women and serum was separated. A high throughput proteomic analysis was performed with the samples collected. Briefly, protein was extracted from the samples and conjugated to a phosphoexplorer antibody array, detected with Cy3- streptavidin, and scanned with a microarray scanner. Using bioinformatic software, significantly differentially expressed proteins of interest have been found in late parous and nulli parous samples when compared to the early parous samples. We have identified the top 20 differentially expressed total (LIMK1, p53, Paxillin, Ret, Tyrosine hydroxylase) and phosphorylated (p14-3-3 theta, p14-3-3 zeta, pCav1, pCD3Z, pDok-1) proteins between the different groups. Several proteins identified using the phosphoexplorer antibody arrays have been validated using Western blots. Overall, this study focuses on the analysis of human breast tissue and serum to gain a deeper understanding of how early parity confers protection against breast cancer.

Citation Format: Christina Gutierrez, Arunkumar Arumugam, Rebecca Lopez, Thiyagarajan Boopalan, Sushmita Nandy, Pamela Agullo, Jacqueline Parada, Susan Love, Rajkumar Lakshmanaswamy. Serum proteomic analysis of early pregnancy-induced protection against breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2573. doi:10.1158/1538-7445.AM2013-2573
Abstract 2576: Novel resveratrol analog ARSHA shows higher potency for inhibiting the growth of triple negative breast cancer cells.
Authors: Chatterjee Anwesha , Ronghe Amruta M. , Singh Bhupendra , Padhye Subhash B. , Bhat Hari K.
Published: August 2014

Resveratrol (Res) (3, 5,

4’-trihydroxystilbene) is a well known naturally occurring polyphenol that exhibits anti-tumor activity. However, its poor bioavailability and rapid metabolism limits its use as a preferred anticancer agent. In an attempt to improve the bioavailability and anticancer potential of Res, we have synthesized five new Res analogs. We then tested the ability of these analogs to inhibit the proliferation of 5 breast cancer cell lines and 3 non-neoplastic breast epithelial cell lines and compared their inhibition potential with

Res. MTT assay for cell proliferation was carried out in human breast cancer and non-neoplastic breast epithelial cell lines. The breast cancer cell lines tested were MCF-7, T47D, MDA-MB-231,

MDA-MB-468 and BT-20. The non-neoplastic breast cell lines tested were MCF-10A,

MCF-10F and HMLE. Of all the analogs tested, one namely ARSHA showed higher potency for inhibiting the proliferation of breast cancer cells compared to

Res. Furthermore, ARSHA showed higher potency for inhibiting the growth of triple negative breast cancer cells (MDA-MB-231, MDA-MB-468 and BT-20) compared to estrogen receptor positive breast cancer cells MCF-7 and T47D. There was neither inhibition nor proliferation by ARSHA of non-neoplastic breast epithelial cell lines tested when compared to vehicle-treated controls.

ARSHA induced Beclin-1 and LC3II which suggest autophagy mediated inhibition of cell growth. Beclin-1 is known to be suppressed in breast cancers and it's over expression is reported to inhibit breast cancer. Results from our studies demonstrate that Res-analog ARSHA is better than Res in inhibiting specifically breast cancer cell growth and shows higher potency for inhibiting the growth of triple negative breast cancer cells by inducing autophagy with an earlier onset for triple negative breast cancer cells. Therefore, ARSHA may be a better chemotherapeutic agent than Res against breast cancer and more specifically against triple negative breast cancer cell growth, a cancer type prevalent in minority African American population with poor prognosis.

Citation Format: Anwesha Chatterjee, Amruta M. Ronghe, Bhupendra Singh, Subhash B. Padhye, Hari K. Bhat. Novel resveratrol analog ARSHA shows higher potency for inhibiting the growth of triple negative breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2576. doi:10.1158/1538-7445.AM2013-2576
Abstract 2577: ARSHA, a novel analog of resveratrol inhibits proliferation of breast cancer cells by modulating expressions of ERα and ERβ.
Authors: Ronghe Amruta M. , Chatterjee Anwesha , Singh Bhupendra , Padhye Subhash B. , Bhat Hari K.
Published: August 2014

Epidemiologic evidence suggests that diets rich in phytoestrogens are associated with a reduced risk of breast cancer. Resveratrol, a bioflavonoid found naturally in grapes, has been very effective as an antiproliferative agent in vitro. However, its poor bioavailability and rapid metabolism limits its use as a preferred anticancer agent.

The problem of poor bioavailability of resveratrol can be solved by the synthesis of its analogs with appropriate chemical modifications that would enhance the stability and anticancer potency of resveratrol. To achieve this objective, we have synthesized a library of resveratrol analogs that resemble the basic skeleton of resveratrol but have structural modifications. These novel analogs were screened for their potential to inhibit growth of breast cancer cells. One analog, namely, ARSHA showed better potential and selectivity in inhibiting the proliferation of breast cancer cells.

Our next goal was to identify the mechanism by which ARSHA specifically inhibits the growth of breast cancer cells. Estrogen receptor (ER) expressing cell lines MCF-7 and T47D, and ER negative cell line MDA-MB-231 as well as ERβ-transfected cell line MDA-MB-231 were treated with 50μM doses of ARSHA for upto 72 hours. mRNA and protein was isolated from respective cell lines. Real-time PCR and western blot analyses were performed. ARSHA significantly induced the expression of ERβ (∼3-fold) and inhibited the expression of ERα (0.2-fold) compared to vehicle treated controls. Taken together, our findings indicate that novel resveratrol analog ARSHA may inhibit the proliferation of breast cancer cell lines by inhibiting the expression of ERα and inducing the expression of ERβ. Estrogen receptor α acts as a mediator of proliferation while ERβ acts as an inhibitor of estrogen signaling.

Citation Format: Amruta M. Ronghe, Anwesha Chatterjee, Bhupendra Singh, Subhash B. Padhye, Hari K. Bhat. ARSHA, a novel analog of resveratrol inhibits proliferation of breast cancer cells by modulating expressions of ERα and ERβ. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2577. doi:10.1158/1538-7445.AM2013-2577
Abstract 2582: In vitro effects of 4-OXO-docosahexaenoic ester on cell signaling in molecular subtypes of human breast cancer cell lines.
Authors: Thompson Henry J. , Jiang Weiqin , Zhu Zongjian , Vanden Heuvel John P. , Amin Shantu , Gowda Krishne , Manni Andrea , El-Bayoumy Karam
Published: August 2014

In vivo preclinical evidence of a heterogeneous effect of n-3 fatty acids (N3FA) on cell signaling pathways associated with the reduced growth of mammary carcinomas (Cancer Res. 2012 Aug 1;72(15):3795-806) is consistent with the expectation that N3FA will not exert uniform effects on all molecular subtypes of breast cancer. Similarly, available evidence indicates that specific metabolites of N3FA are synthesized by mammalian cells and that they exert metabolite specific biological activities. To begin to unravel the complex relationships among molecular subtype specific cell signaling and effects exerted by specific N3FA metabolites on those pathways, a series of proof-in-concept experiments were conducted using cell lines representing 5 molecular subtypes of human breast cancer (BT-474, MCF-7, SKBR-3, MDA-MB-231, MDA-MB-468) and 4-oxo-docosahexaenoic keto ester (4-oxo-DHA), a putative metabolite of docosahexaneoic acid (DHA) that has superior activity to that of DHA in inducing PPARγ activation in vitro. 4-oxo-DHA induced dose dependent inhibition of cell number accumulation of all molecular subtypes but the dose and time responses varied markedly with MCF-7 cells being the least affected and MDA-MB-468 being inhibited to the greatest extent. Detailed mechanistic studies in BT-474, SKBR-3, and MDAMB-463 revealed subtype specific patterns of cell cycle inhibition and apoptosis induction with apoptosis induction dominating in BT-474 and SKBR-3 and inhibition of cell proliferation and apoptosis induction accounting for growth inhibition of MDA-MB-468. While some molecular subtypes were inhibited by mechanisms involving PPARγ activation, others underwent cell growth inhibition via modulation of multiple regulatory nodes in the mTOR signaling network. Evidence is consistent with differential sensitivity among cell types based on whether they are basal or luminal in origin. The experiments described offer a useful complementary approach to the in vivo experiments needed to resolve the N3FA-breast cancer conundrum.

This work was supported by grant KG081632 from the Susan G. Komen Foundation.

Citation Format: Henry J. Thompson, Weiqin Jiang, Zongjian Zhu, John P. Vanden Heuvel, Shantu Amin, Krishne Gowda, Andrea Manni, Karam El-Bayoumy. In vitro effects of 4-OXO-docosahexaenoic ester on cell signaling in molecular subtypes of human breast cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2582. doi:10.1158/1538-7445.AM2013-2582
Abstract 2590: Curcumin inhibits prostate cancer metastasis in vivo by targeting the inflammatory cytokines CXCL1 and -2.
Authors: Killian Peter H. , Kronski Emanuel , Astigiano Simonetta , Barbieri Ottavia , Sommerhoff Christian P. , Nerlich Andreas G. , Pfeffer Ulrich , Bachmeier Beatrice E.
Published: August 2014

In America and Western Europe prostate cancer is the second leading cause of death in men. Emerging evidence suggests that chronic inflammation is a major risk factor for the development and metastatic progression of prostate cancer.

We previously reported that the chemopreventive polyphenol Curcumin inhibits the expression of the pro-inflammatory cytokines CXCL1 and -2 leading to diminished formation of breast cancer metastases. Here we analyse the effects of Curcumin on prostate carcinoma growth, apoptosis and metastasis. We show that Curcumin inhibits translocation of NFκB to the nucleus through the inhibition of the IκB-kinase, IKKβ, leading to stabilization of the inhibitor of NFκB, IκBα, in PC3 prostate carcinoma cells. Inhibition of NFκB activity reduces expression of CXCL1 and -2 and abolishes the autocrine/paracrine loop that links the two chemokines to NFκB. The combination of Curcumin with the synthetic IKKβ inhibitor, SC-541, shows no additive or synergistic effects indicating that the two compounds share the target. Treatment of the cells with Curcumin as wells as siRNA based knock-down of CXCL1 and -2 induce apoptosis, inhibit proliferation, and down-regulate several important metastasis-promoting factors like COX2, SPARC, and EFEMP. In an orthotopic mouse model of haematogenous metastasis, treatment with Curcumin inhibits statistically significantly formation of lung metastases.

In conclusion, chronic inflammation can induce a metastasis prone phenotype in prostate cancer cells by maintaining a positive pro-inflammatory and pro-metastatic feed-back loop between NFκB and CXCL1/-2. Curcumin disrupts this feed-back loop by the inhibition of NFκB signalling leading to reduced metastasis formation in vivo.

Citation Format: Peter H. Killian, Emanuel Kronski, Simonetta Astigiano, Ottavia Barbieri, Christian P. Sommerhoff, Andreas G. Nerlich, Ulrich Pfeffer, Beatrice E. Bachmeier. Curcumin inhibits prostate cancer metastasis in vivo by targeting the inflammatory cytokines CXCL1 and -2. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2590. doi:10.1158/1538-7445.AM2013-2590
Abstract 2591: Global gene expression regulated by phenethyl isothiocyanate in human colon cancer SW480 cells.
Authors: Mi Lixin , Wang Xiantao , Li Xin , Chung Fung-Lung
Published: August 2014

Phenethyl isothiocyanate (PEITC), a promising chemopreventive compound originated from cruciferous vegetables, is known to inhibit proliferation of colon cancer cells through inducing apoptosis and cell cycle arrest. Although exact mechanisms are unclear, it seems that PEITC may have multiple molecular targets and play multiple roles in a variety of events. Some of our recent studies indicate that a key mechanism of apoptosis induction by PEITC may be through covalent modification of its target proteins, such as tubulin. Numerous studies also reported that PEITC may induce apoptotic signals through gene transcriptional regulation. However, systematic studies on PEITC-induced gene expression profile, particularly in colon cancer cells, are rare. In this study, we examined overall gene expression profile of SW480 cells at different time points after PEITC treatment using cDNA microarray. Results showed that PEITC induced significant changes in expression of several apoptosis-related genes, such as BIM, DEDD2, GADD45B, HSPB8, SYK, PIK3C2A, CTNNB1, LGALS8, and NOXA. Furthermore, these changes were confirmed by real-time polymerase chain reaction at transcript level and immunoblot at protein level. Considering significant roles of these genes in signaling transduction leading to downstream events, such as apoptosis, the findings of this study may shed lights on the molecular mechanisms by which PEITC exert its anti-carcinogenic effects. (Supported by NCI grant CA100853)

Citation Format: Lixin Mi, Xiantao Wang, Xin Li, Fung-Lung Chung. Global gene expression regulated by phenethyl isothiocyanate in human colon cancer SW480 cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2591. doi:10.1158/1538-7445.AM2013-2591
Abstract 2592: Helicobacter pylori induces phosphorylation of STAT3 Tyr705 and Ser727 in human gastric epithelial cells.
Authors: Piao Juan-Yu , Lee Hee-Geum , Ji Hyeon-Geum , Han Hyeong-Joon , Ngo Hoang Kieu Chi , Kim Do-Hee , Kim Su-Jung , Lee Sung-Young , Surh Young-Joon
Published: August 2014

Helicobacter pylroi (H. pylori) infection has been considered to be one of the high risk factors of gastritis and gastric cancer, but its pathogenic implication is still poorly understood. Recent studies indicate that constitutive activation of the signal transducer and activator of transcription 3 (STAT3) plays an important role in inflammation-associated carcinogenesis. In our previous study, we found that the phosphorylation of STAT3 at Tyr705 was increased in H. pylori plus high salt diet-induced gastritis in a mouse model. The similar results were observed in human gastric AGS cells co-cultured with H. pylori. Interestingly, H. pylori induced phosphorylation of STAT3 at not only Tyr705 but also Ser727. However, the phosphorylation of two residues exhibited different profiles in human gastric epithelial cells upon H. pylori treatment. The phosphor-Tyr705 increased at early time of H. pylori infection and then decreased immediately, but phosphor-Ser727 increased thereafter which was first discovered in our present study. Phosphorylation of STAT3 is an essential event for inducing the expression of anti-apoptotic/survival proteins, such as Bcl-XL, BcL-2, survivin and c-Myc which contribute to gastric carcinogenesis. Levels of all these proteins were elevated in H. pylori-infected AGS cells. In conclusion, H. pylori induces phosphorylation of STAT3 at both Tyr705 and Ser727 residues. The role of phospohorylation of STAT3 at the Serine 727 residue in H. pylori-induced gastritis and gastric cancer is under investigation.

Citation Format: Juan-Yu Piao, Hee-Geum Lee, Hyeon-Geum Ji, Hyeong-Joon Han, Hoang Kieu Chi Ngo, Do-Hee Kim, Su-Jung Kim, Sung-Young Lee, Young-Joon Surh. Helicobacter pylori induces phosphorylation of STAT3 Tyr705 and Ser727 in human gastric epithelial cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2592. doi:10.1158/1538-7445.AM2013-2592
Abstract 2596: Inhibition of PI3K-mTOR pathway using combination of chloroquine and aspirin regimen leads to apoptosis in pancreatic cancer cells.
Authors: Thakkar Arvind , Grandhi B. Karthik , Wang Jeffrey , Prabhu Sunil
Published: August 2014

Pancreatic cancer ranks as the fourth most deadly form of cancer in the United States with approximately 37,000 deaths each year. The present study aims to evaluate the combinatorial chemopreventive effects of low doses of chloroquine (CQ) and aspirin (ASP) alone and in combination CQA (CQ+ASP) on three pancreatic cancer cell lines, MIA PaCa-2, Panc-1 and BxPC-3. Results demonstrated that low doses of CQ (6.25μM) and ASP (1mM) alone did not reduce cell viability, whereas combination CQA reduced cell viability by ∼80% (P<0.001). CQA combination blocked cell cycle progression at G0/G1 checkpoint. The CQA treatment for 24 h inhibited the NF-κB p50 DNA binding activity by ∼45% (P<0.01) in MIA PaCa-2 and BxPC-3 cells, but no NF-κB inhibition observed in Panc-1 cells. Mechanistic studies revealed that treatment with CQA combination increased the expression of LC3-II protein, indicates inhibition of autophagy. In order to verify the involvement of PI3K and mTOR pathway in CQA-induced apoptosis, we used PI3K inhibitor (3-MA) and mTOR inhibitor (Rapamycin) and analyzed by cell viability assay. The inhibition of PI3K by 3-MA pretreatment enhanced the cell growth inhibition of CQA treatment, whereas the inhibition of m-TOR by rapamycin pretreatment attenuated CQA induced reduction in cell viability. Overall, our results for the first time, illustrate that low dose CQA combinations impart synergistic suppressive activity than chemopreventive agents alone, thus confirming the importance of novel combination chemoprevention strategies against pancreatic cancer.

Citation Format: Arvind Thakkar, B. Karthik Grandhi, Jeffrey Wang, Sunil Prabhu. Inhibition of PI3K-mTOR pathway using combination of chloroquine and aspirin regimen leads to apoptosis in pancreatic cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2596. doi:10.1158/1538-7445.AM2013-2596
Abstract 2597: Prospective study of the relationship between coffee and tea with colorectal cancer risk: The PLCO cancer screening trial.
Authors: Dominianni Christine , Huang Wen-Yi , Berndt Sonja , Hayes Richard B. , Ahn Jiyoung
Published: August 2014

Coffee and tea are commonly consumed and carry several potential anticancer components which could reduce the risk of colorectal cancer risk; however, the relationships of coffee and tea consumption with colorectal cancer risk remain unclear. We prospectively examined the relations of coffee and tea intake to colorectal cancer risk in 53,480 men and women in the intervention arm of the NCI-Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. The majority of these men and women (82.3%) received flexible sigmoidoscopy screening at baseline. Coffee and tea intakes were assessed by a food frequency questionnaire at study baseline. Six-hundred and twenty-two incident colorectal cancer cases were ascertained during a median follow-up of 11.4 years. Greater coffee intake was not associated with risk of colorectal cancer. The relative risks for <1 cup/day, 1 cup/day, 2-3 cups/day and ≥4 cups/day, respectively, were 0.89 (95% CI=0.65-1.20), 0.92 (95% CI=0.68-1.25), 1.02 (95% CI=0.76-1.36) and 1.08 (95% CI=0.78-1.49); p for trend = 0.16. Associations were also not detected for ≥4 cups of coffee/day when stratifying by cancer site (proximal, distal and rectal, p for heterogeneity = 0.53) or stage of disease (stage I, stage II and stage III/IV, p for heterogeneity = 0.86). Furthermore, associations remained unchanged in subsets of participants for either caffeinated or decaffeinated coffee or when stratifying by several colorectal cancer risk factors. Similarly, greater tea intake was not associated with colorectal cancer risk. The relative risks for <1 cup/day, 1 cup/day and ≥2 cups/day were 1.02 (95% CI=0.82-1.27), 1.14 (95% CI=0.83-1.58) and 0.76 (95% CI=0.53-1.10), respectively; p for trend = 0.15. There were also no associations observed for ≥2 cups of tea/day by cancer site (proximal, distal and rectal, p for heterogeneity = 0.79) or stage of disease (stage I, stage II and stage III/IV, p for heterogeneity = 0.44). The associations were also not modified by several colorectal cancer risk factors. In conclusion, the findings of this study do not provide evidence to suggest that drinking coffee or tea is beneficial in protecting against colorectal cancer.

Citation Format: Christine Dominianni, Wen-Yi Huang, Sonja Berndt, Richard B. Hayes, Jiyoung Ahn. Prospective study of the relationship between coffee and tea with colorectal cancer risk: The PLCO cancer screening trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2597. doi:10.1158/1538-7445.AM2013-2597
Abstract 2602: Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signaling.
Authors: Wever Olivier De , Boeck Astrid De , Hendrix An , Denys Hannelore , Braems Geert , Bracke Marc
Published: August 2014

Objective: Bone marrow-derived mesenchymal stem cells (BM-MSC) migrate to primary tumors and drive tumor progression. This study aimed to identify the molecular mechanisms associated with these heterotypic cellular interactions and analyse their relevance in colorectal cancer (CRC).

Design: Paracrine interactions of BM-MSC with CRC cells were studied using collagen invasion assays, cell counts, flow cytometric cell-cycle analysis and tumor xenograft models. The role of neuregulin 1 (NRG1) and the human epidermal growth factor receptor (HER) family pathways were investigated using tyrosine kinase assays, mass spectrometry, pharmacological inhibition, antibody-mediated neutralisation and RNA interference. Transmembrane NRG1 (tNRG1), HER2 and HER3 expression was analysed in primary CRCs (n = 54), adjacent normal colorectal tissues (n = 4), liver metastases (n = 3) and adjacent normal liver tissues (n = 3) by immunohistochemistry.

Results: BM-MSC stimulate invasion, survival and tumorigenesis of CRCs through release of soluble NRG1, activating the HER2/HER3-dependent PI3K/AKT signaling cascade in CRC cells. Tumor-associated mesenchymal cells (T-MC) in CRCs demonstrate high tNRG1 expression. HER2 and HER3 show membrane localization in cancer cells of CRC tissue. High tNRG1 expression in T-MC is significantly associated with advanced UICC stage (P = .005) and invasion depth (P = .04) and decreased 5-year progression-free-survival (PFS) (P = .01).

Conclusion: Paracrine NRG1/HER3 signals initiated by BM-MSC promote CRC cell progression, and high tNRG1 expression is associated with poor prognosis.

Citation Format: Olivier De Wever, Astrid De Boeck, An Hendrix, Hannelore Denys, Geert Braems, Marc Bracke. Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2602. doi:10.1158/1538-7445.AM2013-2602
Abstract 2608: Regulation of response to oxaliplatin by wnt/β-catenin in colon cancer cell lines.
Authors: Lee Myung Ah , Park Jin Hee
Published: August 2014

Background: Oxaliplatin is the standard treatment chemotherapy agent in patients with metastatic colorectal cancer. However, most patients developed the progressive disease after treatment with oxaliplatin due to chemotherapy resistance. Unfortunately the mechanism of resistance of oxaliplatin is unclear. Wnt/β-catenin signaling pathway may play a role in oncogenesis in many cancer and also involve in the control the cancer progression and metastasis throughout the interaction with the tumor microenvironment. In this study, we investigated the response to oxaliplatin regulated by wnt/β-catenin pathway in colon cancer cell line.

Method: We used SNU-C2A and HCT116 human colon cancer cell lines. After comparing β-catenin expression in SNU-C2A and HCT116 cells through western blot, we exposed these two cell lines to gradient concentrations of oxaliplatin for 48hrs to examine the sensitivity. The viability was determined by Neutral Red uptake assay (NR assay). To construct a gene silenced cell line, a siRNA against β-catenin was transfected in HCT116 cells. Besides, we stimulated SNU-C2A cells with human recombinant Wnt3a (rhWnt3a) protein to up regulate the β-catenin and estimated the change of sensitivity for oxaliplatin,respectively. We also constructed a HCT116-cis cell line which showed oxaliplatin-resistance. It has been made by long-term exposure to oxaliplatin.

Result: β-catenin was highly expressed in HCT116 cell line relatively higher than in SNU-C2A cell line. Through the sensitivity test to oxalipatlin, we confirmed that SNU-C2A cells were more sensitive to oxaliplatin than HCT116 cells. When we transfected β-catenin siRNA into the HCT116 cell line, the cell viability was decreased about 20-50% after oxaliplatin treatment. After rhWnt3a treatment,we confirmed the expression of β-catenin and c-myc was up regulated in SNU-C2A cell line by western blot. After treatment with oxaliplatin, we found that the cell viability was reduced in SNU-C2A cells with β-catenin overexpressing. Moreover,HCT116-cis, oxaliplatin-resistance induced cell line, showed not only the increased protein level of β-catenin but also the upper viability for oxaliplatin compared with HCT116.

Conclusion Based on our data, β-catenin is one of the crucial factors to determine the resistance for oxaliplatin in colon cancer cells. Currently we are conducting the analysis with human tissue, and exploring the possible mechanism of resistance developmend to oxaliplatin.

Citation Format: Myung Ah Lee, Jin Hee Park. Regulation of response to oxaliplatin by wnt/β-catenin in colon cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2608. doi:10.1158/1538-7445.AM2013-2608
Abstract 2609: Astrocytes decrease the radiosensitivity of glioblastoma stem-like cells.
Authors: Rath Barbara H. , Camphausen Kevin , Tofilon Philip J.
Published: August 2014

Radiotherapy remains a primary treatment modality for glioblastoma (GBM). However, despite their extensive biological heterogeneity, although some GBMs respond better than others, they all essentially fail radiotherapy. This relatively homogeneous clinical response in a background of inter-tumor heterogeneity suggests that the microenvironment may play a significant role in determining their radioresponse. Data now suggest that glioblastoma stem-like cells (GSCs) play a critical role in GBM development and maintenance. Therefore, towards developing a model system for investigating the role of the microenvironment in GBM radioresponse, we have used human GSCs grown in co-culture with human astrocytes. For these studies GSCs were seeded into the lower compartment of Boyden chambers with astrocytes in the upper compartment. GSC numbers were determined at times out to 18 days after seeding according to ATP content. The proliferation rate of GSCs in co-culture was similar to that obtained when astrocytes were not included in the upper chamber, indicating that astrocytes had no effect on the growth rate of GSCs. To determine whether astrocytes influence GSC radiosensitivity, 48h after co-culture initiation GSCs were irradiated with doses up to 6 Gy; ATP content of the cells were defined 11 days later and radiation survival curves generated. The resulting survival curves showed that the GSCs irradiated under co-culture conditions were significantly less sensitive than those irradiated in the absence of astrocytes. To begin to address the mechanisms responsible for the increased radioresistance of co-cultured GSCs, radiation-induced γ-H2AX nuclear foci were defined in GSCs grown with and without astrocyte co-culture. The initial level of γ-H2AX foci in GSCs was reduced significantly in co-cultures as compared to GSCs cultured in the absence of astrocytes suggesting the induction of fewer DNA double strand breaks. In addition, gene expression profiles generated from GSCs grown in co-culture were significantly different from control GSCs suggesting that astrocytes induced phenotypic modifications. Finally, profiling of astrocyte conditioned media revealed increased levels of a variety of chemokines/growth factors, including a number of which that have already been linked to radioresponse such as HGF, IL-6 and EGF. Taken together, these results are consistent with an astrocyte-mediated radioprotection of GBM cells and provide additional support for a critical role of the microenvironment in contributing to GBM radioresistance.

Citation Format: Barbara H. Rath, Kevin Camphausen, Philip J. Tofilon. Astrocytes decrease the radiosensitivity of glioblastoma stem-like cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2609. doi:10.1158/1538-7445.AM2013-2609