bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4483: Early life exposures and promoter methylation in breast cancer: the Western New York Exposures and Breast Cancer (WEB) Study
Authors: Tao Menghua , Marian Catalin , Shields Peter , Postischman Nancy , Nie Jing , Ambrosone Christine , Edge Stephen , Krishnan Shiva , Vito Dominica , Trevisan Maurizio , Freudenheim Jo
Published: August 2012

Abstract Background: Exposures in the peri- and post-natal period (in utero, infancy, childhood, and adolescence) are associated with breast cancer risk, particularly premenopausal breast cancer. Epigenetic alterations in response to these exposures may play a critical role in early life, and then influence breast cancer risk in adult life. Using archived tumor blocks from incident breast cancer cases in a population-based the Western New York Exposures and Breast Cancer Study (WEB Study), we examined the association between early life exposures and promoter methylation of three tumor suppressor genes (p16, E-cadherin, and RARα2). Method: DNA samples isolated from 803 paraffin embedded tumor tissue were analyzed for hypermethylation status using real time methylation-specific polymerase chain reaction (MSP). Unconditional logistic regression was used for case-case comparisons of those with and without promoter methylation to estimate odds ratios (ORs) and 95% confidence intervals (95% CI) for associations of early life exposure with the likelihood of promoter methylation. Results: Among premenopausal breast tumors, compared to those with normal birth weight (2.6-3.9 kg), there was increased likelihood of E - cadherin gene hypermethylation in tumors from lower birth weight (≥ 2.5 kg) (OR = 2.79, 95% CI, 1.15-6.82). Height was positively associated with the likelihood of hypermethylation of RAR-α2 gene in premenopausal tumors (OR =3.34, 95% CI, 1.19-9.39). For p16, there was significant differences in the likelihood of promoter methylation of p16 in relation to not having been breast fed in premenopausal tumors (OR = 2.75, 95% CI, 1.14-6.62). Among postmenopausal breast cancers, birth order was associated with increased likelihood of p16 promoter methylation. The likelihood of promoter methylation of the individual genes did not differ by maternal age at delivery, maternal height, age at menarche, age of first live birth, and weight at age 20 in either strata of menopause Conclusion: We found lower birth weight, not having been breast fed, and higher height were associated with promoter methylation of E - cadherin, p16 and RAR-α2 premenopausal breast tumors, respectively, suggesting that early life exposures may affect breast carcinogenesis among younger women through aberrant DNA methylation. Further studies of more genes and larger sample size may provide additional insight.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4483. doi:1538-7445.AM2012-4483
Abstract 4573: Enriched driver genes based on histology and smoking status in Asian patients with non-small cell lung cancer
Authors: An She-Juan , Chen Zhi-Hong , Su Jian , Zhang Xu-Chao , Zhong Wen-Zhao , Yang Jin-Ji , Zhou Qing , Yang Xue-Ning , Huang Ling , Guan Ji-Lin , Nie Qiang , Yan Hong-Hong , Mok Tony S , Wu Yi-Long
Published: August 2012

Purpose Patient selection is needed as target therapy had efficacy only to the subsets of patients with specific genetic alterations. We aimed to clarify the subgroups for enriching the patients with candidate driver genes. Patients and Methods The patients who performed clinical genetic tests at Guangdong General Hospital with primary lung cancer were enrolled. Driver genes were detected by sequencing, high-resolution melting analysis, qPCR, or multiple PCR and RACE methods. Results 524 patients were enrolled in this study and the differences of driver genes among subgroups on histology and smoking status were analyzed. In adenocarcinoma with non-smoker subgroup, EGFR mutation was the most frequently altered gene with 49·8%, followed by EML4-ALK (9·3%), PTEN (9·1%), PIK3CA (5·2%), c-Met (4·8%), KRAS (4·5%), and BRAF (1·9%). The three most frequently altered genes in adenocarcinoma with smoker subgroup were EGFR (22·0%), KRAS (12·0), and EML4-ALK (4·5%). We only found EGFR (8·0 %), c-Met (2·8%), and PIK3CA (2·6%) alterations in squamous cell carcinoma (SCC) with non-smoker subgroup. PTEN (16·1%), PIK3CA (7·2%), and EML4-ALK (6·5%) were the three most frequently enriched genes in SCC with smoker subgroup. DDR2 and FGFR2 only presented in SCC with smoker subgroup (4·4% and 2·2%, respectively). Among these four subgroups, the differences of EGFR, KRAS, and PTEN mutations were statistically significant. Conclusion The distinct features of driver genes in different subgroups based on histology and smoking status were very helpful to enrich the patients for guiding the future clinical trials target these genes. The study also suggested that we can consider the patients with infrequently alteration rates of driver genes as an orphan disease and should provide special management model with special molecular targeted therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4573. doi:1538-7445.AM2012-4573
Abstract 4588: Frequency and clinical characteristics of c-MET mutation in malignant melanoma
Authors: Kim Sharon , Gonzalez Nydia , Luthra Raja , Aldape Kenneth , Zuo Zhuang , Liu Ping , Barron David , Kim Kevin B.
Published: August 2012

Purpose: C-MET is over-expressed in metastatic melanoma and have copy number gains at chromosome 7 in late stages of melanoma progression. However, the presence of C-MET mutation is not well known in melanoma. We analyzed tumor samples of patients with malignant melanoma to identify the frequency and the clinicopathology of C-MET mutations. Methods: We identified 103 patients with metastatic mutation who underwent testing for c-MET mutation and reviewed the clinical data of these patients. The sequencing analyses were performed by Sequenom Assay, and the mutations were confirmed with Sanger Sequencing analysis. Clinical characteristics were correlated with C-MET mutation status, and a survival analysis was performed to identify significant associations. Results Among the 103 patients, eleven (11%) patients had melanoma harboring a C-MET mutation. Five (4.5%) patients had N375S mutation; two (1.8%) patients had R988C mutation; two (1.8%) had T1010I; one (1%) patient had H1112R and another patient had N375/T1010 mutation. A median age at diagnosis, sex, race and the status of ulceration at the primary site and the stages at diagnosis were similar between patients with a C-MET mutation and those with wild type. There were no significant differences in the overall survival from the time of stage IV diagnosis between the two groups, but there was a trend of a shorter median duration from the time of the initial diagnosis to distant metastases among patients with a C-MET mutation. (23.6 months vs. 15.9 months, p=0.09). Conclusions We found C-MET mutations in 11% of patients with malignant melanoma. There was a tendency to have distant metastasis at an earlier time in patients with a C-MET mutation. This is the first report describing the frequency and clinical characteristics of C-MET mutations in patients with malignant melanoma.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4588. doi:1538-7445.AM2012-4588
Abstract 4590: Genome-wide identification of possible methylation markers chemosensitive to targeted regimens in colorectal cancers
Authors: Kim Jin Cheon , Lee Han Cheol , Cho Dong Hyung , Choi Eung Young , Cho Yoon Kyung , Ha Ye Jin , Roh Seon Ae , Kim Seon Young , Kim Yong Sung
Published: August 2012

Purpose Few efficient methylation markers of chemosensitivity have been discovered. The genome-wide analysis of methylation markers is needed to identify chemosensitive candidates to targeted therapy. Methods This study describes a two-step process to select chemosensitive candidates of methylation genes. A genome-wide screening of methylation genes was performed using a beadarray and an in vitro chemosensitivity assay of 119 colorectal cancers (CRCs). Results Ten candidate genes identified during the initial screening were verified by biological utility assessment using cell viability assays of transfected CRC cells. Five methylation genes related to sensitivity to bevacizumab regimens (RASSF1, MMP25, KCNQ1, ESR1, and GALR2) or cetuximab regimens (SCL18A2, GPX7, NID2, IGFBP3, and ALX4) were chosen during the first step. A viability assay revealed that GALR2-overexpressing HCT116 cells were significantly more chemosensitive to bevacizumab regimens than control cells (P = 0.022 and 0.019 for bevacizumab with FOLFIRI and FOLFOX, respectively), concurrently verified on a caspase-3 activity assay. GPX7- or ALX4-overexpressed RKO cells were significantly less viable to cetuximab regimens compared to control cells (GPX7: P = 0.027 each for cetuximab with FOLFIRI and FOLFOX; ALX4: P = 0.049 and 0.003 for cetuximab with FOLFIRI and FOLFOX, respectively), but caspase-3 activity was not prominent in GPX7-overexpressed RKO cells. Conclusions Two novel genes, GALR2 and ALX4, have been identified as chemosensitive methylation candidates to bevacizumab and cetuximab regimens, respectively. As our study did not include a clinical association study, the two candidates should be validated in large clinical cohorts, hopefully predicting responsive patients to targeted regimens.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4590. doi:1538-7445.AM2012-4590
Abstract 4592: Sox8 as a molecular marker of oligodendroglial tumors
Authors: Iuchi Toshihiko , Yokoi Sana , Ohira Miki , Kageyama Hajime , Itami Makiko , Hasegawa Yuzo , Kawasaki Koichiro , Sakaida Tsukasa , Nakagawara Akira
Published: August 2012

Backgournd: The precise diagnosis of oligodendroglial tumors from astrocytic tumors is required because the sensitivity to treatments and outcome of patients are different between these two types of gliomas. However, morphological diagnosis of these tumors is not always easy and sometimes different among pathologists. The aim of this study is to clarify the clinical significance of Sox8 as a molecular marker of oligodendroglial tumors. Materials and Methods: The expression level of Sox8 was evaluated by real-time PCR in 74 gliomas (OII: 7, OIII: 15, AIII: 5, GBM: 47), and was compared with morphological diagnosis and other molecular markers as follows: 1p/19q co-deletion evaluated by array CGH, methylation of MGMT gene promoter by methylation-specific PCR, and IDH-1 mutation by immunohistochemistry. For the evaluation of diagnostic value of Sox8-expression, tumors were divided into two groups owing to the expression level of Sox8 (threshold: 2000), and the clinical outcome of patients were compared between these two groups. Furthermore, these diagnostic significances of Sox8 were compared with those of Olig-1 and Olig-2. Results: The expression level of Sox8 was significantly higher in oligodendroglial tumors (p<0.0001), 1p/19q co-deleted tumors (p<0.0001) and tumors with mutant IDH-1 protein (p<0.0001). The frequency of MGMT methylation was higher in tumors with high Sox8-expression, although statistical significance was not proven. In oligodendroglial tumors, the survival of patients with tumors exhibiting high Sox8-expression was significantly better than those with low SOX8-expression (hazard ratio: 6.2, p=0.031). High-expression of Olig-2 (hazard ratio: 4.5, p=0.026) and 1p/19q co-deletion (hazard ratio: 5.1, p=0.020) were also correlated with favorable outcome of patients, but no significant correlation between the expression of Olig-1 and patients’ outcome was observed. Conclusions: Sox8 was highly expressed in 1p/19q co-deleted oligodendroglial tumors. In oligodendroglial tumors, the expression of Sox8 was the significant prognostic factor of patients’ survival.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4592. doi:1538-7445.AM2012-4592
Abstract 4599: Comprehensive molecular oncogenomic profiling & miRNA analysis of prostate cancer
Authors: Sethi Seema , Kong Dejuan , Sakr Wael , Land Susan , Dyson Greg , Sarkar Fazlul
Published: August 2012

Background: Comprehensive molecular oncogenomic and microRNA (miRNA) profiling of tumors can provide tumor specific oncogenomic and miRNA signatures which can be useful to improve diagnostic accuracy, refine prognostic and predictive capabilities, and may serve as therapeutic targets. In prostate cancer (PCa) such a comprehensive analysis has not been reported. Design: DNA and RNA obtained from scant amounts of fresh frozen PCa tumor tissue samples (n=36) were profiled by (1) Mutation analysis: Sequenom Massarray & OncoCarta VI panel that profiles 238 common cancer mutations in 19 oncogenes (known predictors of response or resistance to targeted therapies);(2) Whole-genome gene expression Microarrays: Illumina Chip;(3) Single Nucleotide Polymorphisms (SNP) with genome-wide coverage:Illumina Omni microarrays. (4)miRNA analysis was done on RNA from FFPE PCa tumor tissues (n=126) using RT-PCR. Data was statistically analyzed & correlated with clinical & pathologic variables. Results: Massarray analysis identified a MET oncogene mutation, variant T992I, in a 49 year old patient with Gleason score 7 (4+3) tumor. Of the 47,224 genes analyzed by gene expression microarrays, 74 genes were significant predictors of high tumor grade by ordinal regression analysis (p<0.0001). TGIF1 was the most significant gene. Of the 731,442 SNP's analyzed, 638 significantly predicted high tumor grade by logistic regression analysis (p<0.0001). There was significant interaction between gene and SNPs in 531 SNP/gene pairs (p<0.05). Ingenuity Pathway analysis revealed the significant predictor genes (p<0.05) were involved in biological pathways for Gene Expression, Cell Cycle, Cancer,” “Inflammatory Response, Cell Death, Infection Mechanism & Cellular Assembly, Organization, Gene Expression, Cancer. P53 gene was found to be at the center hub of significant predicting pathways. Loss of miR-34a expression was found in PCa tissues consistent with the central role of p53. Conclusions: Using high throughput genomic profiling & miRNA analysis of small amounts of fresh-frozen and FFPE PCa tumor samples, we identified clinically relevant hot spot mutation in MET oncogene and several significant genes & SNPs to predict tumor grade. P53 gene is at the center hub of all significant pathways. Loss of miR-34a was consistent with p53 function in PCa. MET oncogene mutation is a novel finding, not previously reported in PCa against which small molecule inhibitors are under development. These molecular signatures may have a significant clinical impact on improving diagnostic and predictive capabilities & in designing targeted therapies to achieve the goal of personalized medicine.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4599. doi:1538-7445.AM2012-4599
Abstract 4601: The role of nicotine-induced oxidative stress in oral cancer cells
Authors: Tang Xiaofei , Zhang Yanhua , Zhang Min
Published: August 2012

Objective To investigate the role of nicotine-induced oxidative stress in SCC15 oral cancer cells. Methods The growth, apoptosis, ROS level, Prx1 expression and NF-αb DNA binding activity were detected in SCC15 oral cancer cell using MTT assay, RT-PCR, Western blotting, flow cytometry, ELISA. Results The ROS level was elevated in SCC15 cells treated with nicotine for 24h at different concentrations (0.1μM, 1μM, 10μM). Cell growth was induced by nicotine for 24h, 48h at different concentrations. Few SCC15 cells were induced apoptotic cell death treated with nicotine for 24h, there was no obvious changes in cell apoptosis for 48h, 72h, compared with control. Prx1 mRNA and protein expression were up-regulation treated with nicotine. NF-αb DNA binding activity was increased treated with nicotine for 24h, 48h, 72h. Conclusion Nicotine induced oxidative stress and cell proliferation, which maybe regulated by Prx1/NF-αb axis in oral cancer cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4601. doi:1538-7445.AM2012-4601
Abstract 4605: Neurotrophin system expression in human lung cancer stem cells
Authors: Mancini Rita
Published: August 2012

The availability of in vitro and in vivo systems which reproduce the natural heterogeneity of spontaneous human cancers is of critical importance to assess the potential of new combination treatments and to establish better correlations between molecular signatures and response to therapy. We have focused our attention on the subset of non small cell lung cancers (NSCLC) classified as Lung Adenocarcinomas (AdenoCa) which account for approximately 40% of lung cancer cases and have recently reported that Malignant Pleural Effusions (MPEs) represent an excellent source to culture a wide variety of Lung AdenoCa cells from different donors (Mancini et al, PlosOne, 2011). Reproducible protocols for rapid cancer cell isolation from MPEs and growth in adherent and spheroid conditions have been established in our lab. In order to avoid long periods of adaptations in cell culture that may lead to the selection of subpopulation of cells with particular growth advantages all samples are banked at early passages, on average one month following MPE collection. Furthermore we have observed that these cells can achieve efficient tumor engraftment in recipient NOD/SCID mice, also upon inoculation of small number of cells, thus suggesting indirectly the presence of tumor initiating cells. We believe to have a set up solid system for the study of AdenoCa biology. Recently, we have started to study the expression of neurotrophins (NTs) in cultured lung adenocarcinoma cells from malignant pleural effusion. Using enzyme-linked immunosorbent assays in cancer stem cells and adherent cells from the same patients we have detected nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3), and their levels are higher as compared with adhesion and spheroid cells. We have documented, using molecular biology and immunocytochemistry, a different expression of the NTs and their cognate receptors, in lung cancer stem cells in comparison with differentiated cancer cells. Furthermore, the expression on these peptides resembles the previously documented pattern demonstrated in human embryonic stem cells. These data further support the possible role of NTs in cancer cell behavior.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4605. doi:1538-7445.AM2012-4605
Abstract 4608: RRBP1 overexpression is frequently found In lung cancer patients and alleviates intracellular stress induced apoptosis through positive regulation of GRP78 in lung cancer
Authors: Tsai Hong-Yuan , Hsiao Michael
Published: August 2012

How tumors evade apoptotic signals and survive during cancer progression has not yet been resolved. To unravel the molecular mechanisms involved in lung carcinogenesis will greatly improve therapy. Endoplasmic reticulum is a cellular organelle in which secretory and proteins are synthesized and modified. These processes are always enhanced in cancer cells. Ribosome binding protein1(RRBP1) was originally reported as a ribosome-binding protein on the rough endoplasmic reticulum. In this report, we showed that RRBP1 was highly expressed in the early stage of lung cancer compared to their adjunct normal tissue samples by utilizing lung cancer tissue array(n=87). Depletion of RRBP1 by short-hairpin RNAs significantly reduced cell growth and induced apoptosis in A549 and CL1-5 cells, but not in normal lung cells(BEAS2B). Furthermore, RRBP1-depleted NSCLC cells could activate CD95/caspase signaling pathways. Treatment with caspase8 inhibitor (ZVAD-FMK) or with shRNA against caspase8 was sufficient to suppress apoptosis in RRBP1-depleted cells. This effect is associated with significantly reduction in the expression of GRP78. GRP78, an antiapoptotic protein widely upregulated in cancer, plays a critical role in chemotherapy resistance in some cancers. According to our data, ectopic expression of RRBP1 alleviated tunicamycin induced apoptosis by upregulation GRP78 protein level in lung cancer cells. A strong correlation was observed between the expression of RRBP1 and GRP78 in tumor biopsies from NSCLC patients, supporting the concept that GRP78 expression levels are controlled by RRBP1. Taken together, this study not only showed that GRP78 is regulated by RRBP1 but also report that RRBP1 and GRP78 expression is involved in NSCLC growth and progression. suggest that RRBP1 is required for lung cancer growth and development, which may be a useful target in lung cancer treatment and expected to provide the basis for a rational approach for the development of new molecular targeted therapies

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4608. doi:1538-7445.AM2012-4608
Abstract 4611: Cancer reversal by dual strategy: A new molecular target?
Authors: Gosalvez Mario G.
Published: August 2012

Haste is a bad counselor when one is striving to address important issues. The new technique, which I draw your attention to, was first started in the 1980's and was completed in 2010 (Gosalvez, M. Thioproline and the reversal of cancer. The Lancet, p. 1108, May 14 1983. M Gosalvez. Mitochondrial Filamentation. AACR 101 Meeting. April 2010. Washington, USA). Throughout these 30 years several molecular targets for a cancer cure have been developed. The last hope, despite countless efforts, malignant neoplasia genetic therapy, has not yet consolidated itself. We trust that our colleagues, dedicated to therapeutic experimentation on human beings, will now address this new possibility, either alone, or in combination with other efforts. Better agents than Quelamycin (Cortes-Funes H, Brugarolas A and Gosalvez M. Quelamycin: A summary of Phase I Clinical Trials. Recent Results in Cancer Research, 74, 200-206, 1980. Eds. G Mathe and FM Muggia, Springer-Verlag. Germany) and Thioproline (Brugarolas A and Gosalvez M. Preliminary clinical results with Norgamem (thioproline) and Revercan (2-amino-2- thiazoline): The first inducers of reverse transformation. In: “Adjuvant Therapies of Cancer”. Mathe, Bonnadona and Salmon Eds.Springer-Verlag, Germany.1982, 346) can be gathered, with the precise cronotherapeutic emphasis, by correctly measuring the mobility (Gosalvez M, Blanco M, Bueno M and Balaguer R. Treatment of Leukaemia 1210 intravenous transplants with tumour modifiers, redoubt cytotoxics and minor tranquilizers, Lubec G and Rosenthal GA Eds. In: “Aminoacids. Chemistry, Biology and Medicine”. Escom Sciences Publishers, 704-711, 1990. Gosalvez, M. Reversal of Cancer by Dual Strategy. Madrid. Editorial Gober. 1992) of the patients under study. Now, after sufficient time has elapsed for the consideration of previous propositions, which have only had partial success, perhaps now the right moment has arrived for our proposal. We believe that, after a few years, the light at last will be seen at the end of the tunnel of suffering for patients and their families. If this proves to be the case, we could now, with the collaboration of everyone, tackle the possibility of using cancer as a therapeutic agent. All the sciences around our problem demand a great commitment for all involved.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4611. doi:1538-7445.AM2012-4611
Abstract 4612: Overexpression of cholesterol metabolism regulatory gene farnesyl diphosphate farnesyltransferase is associated with poor prognosis of non-small cell lung cancer patient and promotes metastasis through feedback regulation of SPP1-PI3K-AKT signaling pathway
Authors: Yang Yi-Fang , Tsia Hong-Yuan , Lee Chien-Hsin , Lim Christina H , Hsiao Michael
Published: August 2012

Lung cancer is the leading cause of the human cancer-related death in the world and non-small cell lung cancer (NSCLC) accounts for up to 80 % of those patients. Cholesterol metabolism is especially active in cancer cells, whereas cholesterol synthesis inhibition has been show to reduce tumor cell growth. However, the involvement of farnesyl diphosphate farnesyltransferase (FDFT1) in lung cancer development and progression remains unclear. FDFT1 was involved in cholesterol biosynthesis. In this study, we investigated the clinical significance and biological effects of FDFT1 in NSCLC. Immunohistochemical studies performed on 141 primary NSCLC specimens revealed a high prevalence of FDFT overexpression (51%), which was significantly associated with lymph node metastasis (regional, P = 0.022), advanced tumor stage (P = 0.004), and poorer disease-free survival (P = 0.001, log-rank test; P = 0.001, Cox proportional hazard model). FDFT1 down-regulation by two shRNAs significantly reduced cell migration and invasion in highly invasive lung cancer cell lines in vitro, as well as lung metastases in vivo. Conversely, overexpression of FDFT1 in weakly invasive lung cancer cell lines in vitro and orthotopic metastasis assay in vivo shows enhanced cell motility and lung metastases. In addition, inhibition of FDFT1 decreased AKT activation and thereby suppressing the migration of human lung cancer cell in vitro. The results suggested that FDFT1 can positive feedback to regulate AKT. In weakly invasive lung cancer cell lines, FDFT1 overexpression was associated with the upregulation of secreted phosphoprotein 1(SPP1). The shRNA mediated knockdown of SPP1 was found to block FDFT1-enhanced invasion. Taken together, we have identified cholesterol metabolism regulatory gene FDFT1 as a cancer progression biomarker who overexpression leading to poor prognosis and result tumor metastasis feedback regulation of SPP1-PI3K-AKT signaling pathway.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4612. doi:1538-7445.AM2012-4612
Abstract 4616: Age dependent increase in Prostaglandin pathway coincides with onset of ovarian cancer in laying hens
Authors: Eilati Erfan , Pan Lurui , Bahr Janice M. , Hales Dale Buchanan
Published: August 2012

The link between chronic inflammation and cancer has been recognized for many years. Cyclooxygenase (COX) (PTGS) is the rate limiting enzyme in catalyzing the conversion of arachidonic acid to prostaglandins. Two isoforms of cyclooxygenase has been identified, COX-1 and COX-2. Ovarian cancer is the fifth leading cause of cancer death among women and the most lethal gynecological malignancy. Ovarian cancer is mainly seen in older women when their ovaries are not reproductively functional. Hens spontaneously develop ovarian adenocarcinomas that are similar in histological appearance to human ovarian carcinomas and share similar symptoms of the disease thus the laying hen is the only accessible animal model that recapitulates human ovarian cancer. Many hypotheses about etiology of ovarian cancer have been proposed but the factors that contribute to correlation of age and ovarian cancer are unknown. The purpose of this study was to examine the expression of inflammatory factors and compare them to age. White Leghorn hens aged 12-45 months were used. The incidence of ovarian cancer was determined by gross pathology and histology. COX-1 and COX-2 mRNA were extracted from ovarian tissue, preserved in RNAlater and their expression was determined using quantitative real-time PCR (qRT-PCR). Protein of both COX enzymes was isolated from ovarian tissue frozen in liquid nitrogen and were analyzed by Western blot. Ovarian tissue fixed in neutral buffered formalin was used for histology. Prostaglandin E2 amounts was measured in frozen ovarian tissues using ELISA. A significant increase in the incidence of ovarian cancer with age in laying hen was detected. The expression of both COX-1 and COX-2 protein and mRNA was remarkably increased in older hens compared to younger hens. In correlation with increased ovarian cancer incidence, expression of both COX enzymes and PGE2 concentration were elevated significantly with age. Our finding suggests that the up-regulation of COX mRNA and protein levels with age is the main contributing factor in the age associated increase in prostaglandin E2. The present study provides the first insight into the age-related changes in the expression of COX-1, COX-2 and prostaglandin E2. The results of current study demonstrated that PGE2 was elevated in ovaries of hens concomitant with age indicating its possible role in initiation and/or progression of ovarian malignancies. These finding may provide the basis for clinical trials utilizing COX specific inhibitors or dietary intervention targeting prostaglandin biosynthesis for the treatment and prevention of ovarian cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4616. doi:1538-7445.AM2012-4616
Abstract 4631: Anti-CD70 antibody-drug conjugates containing pyrrolobenzodiazepine dimers demonstrate robust antitumor activity
Authors: Jeffrey Scott , Burke Patrick , Meyer David , Lyon Robert , Miyamoto Jamie , Anderson Martha , Stone Ivan , Law Che-Leung , Senter Peter
Published: August 2012

Antibody-drug conjugates (ADCs) represent an important approach for the selective delivery of highly potent small molecules to malignant cells. Recently, we have adapted the highly cytotoxic class of minor groove DNA crosslinking agents, pyrrolobenzodiazepine dimers (PBDs), in order to conjugate them to monoclonal antibodies. These totally synthetic molecules alkylate guanine bases in a sequence-specific manner to cause cell death at pM concentrations. In this report, we describe for the first time a novel PBD that can be stably conjugated to the anti-CD70 monoclonal antibody (mAb) h1F6 via maleimide conjugation to engineered cysteine residues created by the single amino acid substitution S239C on each heavy chain. This results in a uniform loading of two drugs per antibody. The resulting ADC binds selectively to CD70 on renal cell carcinoma cell lines and releases the free drug upon internalization and cleavage of the dipeptide linker in the lysosome. The ADC retains the robust cytotoxicity of the free drug, displaying immunologically selective antitumor activity in xenograft models at well tolerated doses as low as 0.1 mg/kg. The PBDs represent a promising new class of cancer drugs for targeted delivery.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4631. doi:1538-7445.AM2012-4631
Abstract 4657: Differential regulation of autophagy vs. apoptosis as a potentially unique mechanism of cancer cell specific radiosensitization with fluoxetine
Authors: Moran-Guiati Nicci P.
Published: August 2012

Introduction: Prior data demonstrate that selective serotonergic reuptake inhibitors (SSRIs) are cytotoxic to cancer cells and that fluoxetine can sensitize cells to radiotherapy (XRT) potentially through induction of autophagy; however, there is limited information on the effects of serotonergic receptor modulation and mechanisms of other SSRIs on cytotoxicity with radiotherapy. Methods: Human lung cancer lines (A549 and H460) and oropharyngeal cancer cells (FaDu) were treated with dose escalated SSRIs (fluoxetine, sertraline, paroxetine), serotonergic receptor (5-HTR) agonists (CP809101, S14506), or 5-HTR antagonists (agomelatine, spiroxatrine) alone or in combination with dose escalated XRT to evaluate the effects of on cell survival using clonogenic survival assays. 5-HTR expression, apoptosis, and autophagy were evaluated as potential mechanisms of the effects of SSRIs on XRT. Results: Fluoxetine, paroxetine, or sertraline alone had a cytotoxic effect on cancer cells in a concentration dependent manner. Fluoxetine had a sensitizing effect in combination with XRT in a cell specific manor; however, sertraline and paroxetine had an additive cytotoxic effect on XRT. 5-HTR agonists and antagonists did not demonstrate any significant sensitizing effects, but agonists were cytotoxic at 10-50 uM with no apparent cytotoxicity from antagonists. Western blot analysis demonstrated that fluoxetine, paroxetine, or sertraline decreased apoptosis (cleaved caspase-3 and cleaved PARP) and increased autophagy (LC3B-II) in H460 cells associated with the sensitizing effect of fluoxetine on XRT. In contrast, the additive cytotoxicity of sertraline or paroxetine was not associated with a differential regulation of apoptosis vs. autophagy in A549 cells. Conclusions: SSRIs appear to have a cytotoxic effect alone or in combination with XRT potentially through a non 5-HTR based mechanism. The cell specific differential regulation of apoptosis vs. autophagy associated with fluoxetine warrants further examination of a potentially unique mechanism of radiosensitization.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4657. doi:1538-7445.AM2012-4657
Abstract 466: Synthetic triterpenoids target cell migration and cell adhesion via GSK3β
Authors: To Ciric , Di Guglielmo Gianni M.
Published: August 2012

Synthetic triterpenoids are a class of anti-tumor compounds that target various cellular functions including apoptosis, growth inhibition, anti-inflammation and cytoprotection. Previously, we have shown that triterpenoids also inhibit cell migration and the objective of our current study is to examine the molecular mechanisms. Since cellular adhesion dynamics play a critical role in cell migration, we investigated the effects of triterpenoids on focal adhesion morphology. Using immunofluorescence microscopic analysis of focal adhesion markers, paxillin and Focal Adhesion Kinase (FAK), we found that cells that were treated with synthetic triterpenoids possessed enlarged focal adhesions. Interestingly, numerous focal adhesion related proteins including IQGAP1, paxillin, FAK and Glycogen Synthase Kinase 3 (GSK3) were identified as drug-binding proteins using pull down and mass spectrometry approaches. Therefore, we investigated if triterpenoids target these proteins and affect cell adhesion turnover to inhibit cell migration. We found that focal adhesion re-establishment was altered by triterpenoids while pre-existing focal adhesions remained largely unaffected. To further explore the underlying mechanism of triterpenoids on GSK3β dependent cell adhesion dynamics, we analyzed GSK3β activity. We found that triterpenoids stimulate the phosphorylation of GSK3β at serine 9, however, both FAK and paxillin phosphorylation was largely unaffected by the triterpenoids. In parallel studies, we observed that focal adhesion staining was enlarged with cells that were treated with the GSK3β inhibitors, lithium chloride and SB216763. In addition, GSK3β inhibition affected the localization of not only GSK3β but also IQGAP1, an important scaffolding protein involved in cell polarity. From our results, we postulate that synthetic triterpenoids may affect cell migration by targeting GSK3β, which in turns, inhibits its activity and displaces its localization from the leading edge. More importantly, GSK3β inhibition by the triterpenoids and by GSK3β inhibitors also lead to the displacement of IQGAP1 from the leading edge, which further suggests that triterpenoids may act via a GSK3β mechanism to affect focal adhesions and cell migration.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 466. doi:1538-7445.AM2012-466
Abstract 4799: Identification of drug resistance targets in ovarian cancer using a proteomic approach
Authors: Cruz Isa , Angelino Rita , Coley Helen , Schatzlein Andreas , Yang Min
Published: August 2012

Ovarian cancer ranks first in the number of deaths and second in the number of new cases among gynecological cancers. In the majority of the cases, surgery is the intervention of choice, but chemotherapy has progressed considerably over the last years. First-line treatment for advanced-stage disease is a combination of carboplatin and paclitaxel. However, drug resistance has become a major obstacle to the successful chemotherapeutic treatment of human cancers. Currently, there is no clear consensus on treatment options for ovarian cancer patients who acquired drug resistance, due to the lack of knowledge about drug resistance mechanisms. There is an urgent need to explain how drug resistance occurs and to identify proteins related to this phenomenon, so that inhibitors can be designed. The aims of this study are to develop and optimise a two-dimensional gel electrophoresis method to compare protein profile of human ovarian cancer cell lines, which are sensitive or resistant to anticancer chemotherapy, so that proteins related to drug resistance can be identified using mass spectrometry. The parental ovarian cancer cell line models PEO1 and SKOV-3 are used as drug sensitive reference cell lines. Novel drug resistant models, derived from the parental lines, with in vitro acquired resistance to paclitaxel and carboplatin are used alongside their respective drug sensitive parental counterparts. Proteins related to tumorigenesis or drug resistance, either new or previously reported, were identified in at least one of the three cell lines. These proteins belong to different classes and are responsible for distinct functions within the cell, such as cytoskeleton and cell structure, detoxification and stress response, and cellular metabolism. This is the first proteomic study on these specific ovarian cancer cell lines using paclitaxel and carboplatin. The results obtained will be useful for further studies of resistance mechanisms and screening of resistance biomarkers for the development of tailored therapeutic strategies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4799. doi:1538-7445.AM2012-4799
Abstract 4801: p90/CIP2A may play a role in regulating the phosphorylation of CREB1 in cancer
Authors: Peng Bo , Lei Ningjing , Peng Xuanxian , Qian Wei , Tan Eng M. , Zhang Jianying
Published: August 2012

Cancerous inhibitor of PP2A (CIP2A) is a tumor-associated autoantigen migrating in SDS-PAGE as a protein of 90kD (also called p90). This protein was shown to be expressed in the mouse embryonic stage but inactivated in adult tissues. It has been shown to inhibit PP2A function thus stabilizing the oncogene c-myc in human malignancies. In the present study, we used two-dimensional electrophoresis-based approach and identified 47 differentially expressed proteins upon the loss of p90/CIP2A in H1299 lung cancer cell line. Among these 47 proteins, 30 proteins have been well documented to be associated with cancer, of which 12 proteins are up-regulated and 18 proteins are down-regulated after knock-down of p90/CIP2A via shRNA. To investigate whether these proteins are associated with any known cancer-related pathway, differentially expressed proteins were analyzed using Pathway Studio bioinformatics software. The resulting data indicated that four possible transcription factors (c-myc, ESR-1, ETS-1 and CREB) may involve in the regulation of the differentially expressed proteins. Further studies showed that down-regulation of p90/CIP2A may affect CREB phosphorylation: treatment with serum induced less phosphorylation of CREB in cells transduced with p90/CIP2A shRNA than the cells tranduced with control shRNA. However, other treatments like KCl and forskolin did not show significant difference between these two groups. We also found that the phosphorylation of the CREB upstream kinase, AKT, was also down-regulated while other kinases p38 and p90RSK was unaffected. These preliminary data imply that p90/CIP2A may target AKT-CREB pathway to promote cell proliferation in a c-myc independent manner.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4801. doi:1538-7445.AM2012-4801
Abstract 4817: Using the Mendelian randomization approach to clarify the role of well-done meat and heterocyclic amine exposure in the etiology of colorectal polyps
Authors: Fu Zhenming , Shrubsole Martha J. , Li Guoliang , Cai Qinyin , Smalley Walter E. , Hein David W. , Chen Zhi , Shyr Yu , Ness Reid , Zheng Wei
Published: August 2012

Background: High red meat intake and meat-derived mutagen heterocyclic amines (HCAs) exposure have been linked to the risk of colorectal polyps and cancer. HCAs are activated and detoxified by a group of carcinogen metabolizing enzymes. Internal exposure dose to these carcinogens is determined by both external exposure and genetic polymorphisms in genes encoding these enzymes, providing a unique opportunity to conduct a Mendelian randomization analysis to reduce bias associated with observational epidemiological studies. Methods: In a colonoscopy-based case-control study, we recruited 5,386 participants, including 2,057 patients with colorectal polyps, and 3,329 polyp-free controls. Twenty single nucleotide polymorphisms (SNPs) were analyzed to construct a HCA metabolizing score. Data on dietary intake of meat by cooking methods and doneness level were obtained through telephone interviews to derive dietary HCA exposure level. Interactions between HCA metabolizing score and dietary exposure variables were evaluated using multivariate unconditional logistic regression models to derive odds ratios (ORs) and 95% confidence intervals (CIs). Results: HCA metabolizing score was unrelated to polyp risk among those with a low intake of total meat or red meat and low dietary HCA exposure. These dietary variables also tended to not be associated with polyp risk among those with a low HCA metabolizing score. Risks of polyps associated with meat intake and HCA exposure, however, were elevated among those with a high risk HCA metabolizing score. The interactions between dietary meat exposures and HCA metabolizing score were statistically significant for most of the analyses (P α0.05). Participants with the highest meat intake and HCA exposure level and a high risk HCA metabolizing score had a 30% to 40% elevated risk of developing any polyps and 60% to 80% elevated risk of developing advanced or multiple adenomas. Conclusions: Dietary meat intake and dietary exposure to HCAs is associated with an elevated risk of colorectal polyps, and this association is modified by genetic polymorphisms in HCA metabolizing enzymes. This study provides strong evidence supporting a causal role of HCA exposure in the etiology of colorectal tumors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4817. doi:1538-7445.AM2012-4817
Abstract 4836: Inhibition of PI3K/mTOR leads to adaptive resistance in extracellular matrix attached cancer cells
Authors: Muranen Taru E. , Selfors Laura , Worster Devin , Iwanicki Marcin , Song Loling , Morlaes Fabiana , Mills Gordon B. , Brugge Joan S.
Published: August 2012

The PI3K/mTOR-pathway is the most commonly deregulated pathway in epithelial cancers and represents an important target for cancer therapeutics. Here we show that inhibition of PI3K/mTOR in ovarian and breast cancer 3D spheroids leads to death of inner extracellular matrix-deprived cells, whereas matrix-attached cells are resistant. Resistance to PI3K inhibitors is associated with upregulation of a cellular survival program that involves both FOXO-mediated transcription and a novel translational resistance mechanism. This program is evolutionarily well-conserved and resembles nutrient/growth deprivation, leading to translation of IRES-containing pro-survival mRNAs, previously associated with cellular stress responses. Inhibition of any of several upregulated pro-survival proteins, including Bcl-2, EGFR, or IGF1R, abrogates resistance to PI3K/mTOR inhibition in breast and ovarian cancer cells and ovarian cancer xenografts. These studies provide a platform for rational development of effective drug combinations through the use of 3D-based model systems together with high-throughput proteomics approaches and identify drug combinations for further analysis as cancer therapeutics.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4836. doi:1538-7445.AM2012-4836