bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A108: Phosphoprotein network activation during breast cancer initiation
Authors: Seewaldt Victoria L. , Ibarra-Drendall Catherine , Pilie Patrick , Barry William , Broadwater Gloria , Petricoin Emanuel
Published: January 2011

Background: Currently we lack the ability to rapidly test new agents to prevent breast cancer. Targeted agents are in clinical testing for treatment of breast cancer but are not being adequately explored for prevention. This is because, without biomarkers to select women that are most likely to respond and rapidly evaluate response, Phase I/II testing of targeted agents for prevention will be too risky and expensive. Single biomarkers have been traditionally used to evaluate response to chemotherapeutic agents. However, single biomarkers may not be adequate to evaluate the complex phosphorylation network signaling events that occur during breast cancer initiation. Furthermore, emerging evidence suggests that resistance to targeted agents may occur through paradoxical activation of quiescent signaling pathway. As a result, it has become increasingly important to monitoring network signaling in women receiving targeted agents.

Targeted agents that have low-toxicity profiles and have inhibitory activity against breast cancer cell proliferation and/or invasion may show promise as a prevention agent. However, before any given targeted agent could be tested for pilot prevention trials, we first need to identify 1) signaling pathway(s) that are affected by the drug in preclinical models of breast cancer, 2) short-term and long-term consequences of treatment, 3) potential biomarker(s) to closely track response.

Methods and Results: We tested for protein network signaling in cytological specimens in women at high-risk for breast cancer. Our group used reverse-phase protein microarray (RPPM) platform to test for proteomic signatures of short-term risk to breast cancer. RPPM was developed to provide reproducible assessment of 50 phospho-proteins in 5,000 epithelial cells. Initial signature testing was performed in mammary cytology obtained from two groups of 50 high-risk women undergoing Random Periareolar Fine Needle Aspiration (RPFNA). Unsupervised heirachal clustering of RPPM proteomic analysis RPFNA aspirates from high-risk women identified three activated signaling pathways 1) Akt/mTOR/PI3K/cSrc, 2) EGRF/MEK/ERK, and 3) HER2/bcl-2.

Conclusion: Here we demonstrate our ability to identify activated phospho-protein signaling pathways in limited RPFNA cytology. The power of this approach is that we can use a combination of RPPM and RPFNA to track response to any new targeted prevention agents. Importantly, we are able to validate our proteomic signatures in parallel nanobiosensor testing of live atypical RPFNA cytology from women in our high-risk cohort.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A108.
Abstract A13: Short-chain fatty acids (SCFA) induced autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death
Authors: Tang Yong , Chen Yakun , Jiang Hongmei , Nie Daotai
Published: January 2011

Short-chain fatty acids (SCFAs) are the major by-products of bacterial fermentation of undigested dietary fibers in the large intestine. SCFAs, mostly propionate and butyrate, inhibit proliferation and induce apoptosis in colon cancer cells, but clinical trials had mixed results regarding the anti-tumor activities of SCFAs. Herein, we demonstrate that propionate and butyrate induced autophagy in human colon cancer cells to dampen apoptosis whereas inhibition of autophagy potentiated SCFA-induced apoptosis. Colon cancer cells, after propionate treatment, exhibited extensive characteristics of autophagic proteolysis: increased LC3-I to LC3-II conversion, acidic vesicular organelle development, and reduced p62/SQSTM1 expression. Propionate-induced autophagy was associated with decreased mTOR activity and enhanced AMP kinase activity. The elevated AMPKalpha phosphorylation was associated with cellular ATP depletion and overproduction of reactive oxygen species due to mitochondrial dysfunction involving the induction of MPT and loss of membrane potentials. In this context, mitochondria biogenesis was initiated to recover cellular energy homeostasis. Importantly, when autophagy was prevented either pharmacologically (3-MA or chloroquine) or genetically (knockdown of ATG5 or ATG7), the colon cancer cells became sensitized toward propionate induced apoptosis through activation of caspase-7 and caspase-3. The observations indicate that propionate-triggered autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death, whereas application of an autophagy inhibitor (Chloroquine) is expected to enhance the therapeutic efficacy of SCFAs in inducing colon tumor cell apoptosis.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A13.
Abstract A19: The Srx-Prx IV axis promotes human lung cancer progression through modulation of specific phosphokinase signaling
Authors: Wei Qiou , Jiang Hong , Xiao Zhen , Baker Alyson , Young Matthew R. , Veenstra Timothy D. , Colburn Nancy H.
Published: January 2011

Oxidative stress is known to cause tumorigenesis through induction of DNA and lipid damage. It also promotes tumor progression through a largely unknown mechanism. Sulfiredoxin (Srx) is an oxidation-induced antioxidant protein that catalyzes the reduction of hyperoxidized peroxiredoxins (Prxs) to the reduced form to restore their peroxidase activity. Our previous study demonstrates that Srx is a novel target of activator protein-1 (AP-1) activation and TAM67 (a dominant negative form of c-Jun) inhibition. However, the role of Srx in cell signaling and cancer development has not been well-studied. In this study, our goal is to investigate the function and molecular mechanism of Srx in human lung cancer.

Our current work demonstrates an important oncogenic role of Srx in cancer maintenance and progression through the Srx-Prx IV axis and the modulation of specific phosphokinase signaling cascades. First, tissue microarray was used to evaluate Srx expression in human primary lung cancer tissues. We found that Srx is highly expressed in lung squamous cell carcinoma and adenocarcinoma, but not in the normal lung. By knockdown of Srx in human lung cancer A549 cells, we discovered that Srx is required for anchorage independent colony formation, cell migration and invasion of A549 cells. Second, using immunoprecipitation and mass spectrometry, we identified proteins that interact with Srx. Surprisingly, we found that Prx IV was the predominant protein that interacts with Srx. Using purified recombinant proteins and surface plasmon resonance techniques, we demonstrated that Srx has a higher binding affinity to Prx IV than to other Prxs. Third, we found that knockdown of Prx IV, but not other Prxs, recapitulated the phenotypic outcomes of depleting Srx in A549 cells. In addition, when injected into SCID mice, disruption or enhancement of the Srx-Prx IV axis leads respectively to reduction or acceleration of mouse tumor growth and lung metastasis formation. Furthermore, proteome profiler phosphokinase assay revealed that activation of specific phosphokinase signaling cascades, including AP-1, CREB and MAPK signaling, was dependent on the integrity of the Srx-Prx IV axis. In summary, our findings demonstrate a novel oncogenic role of the Srx-Prx IV axis in human lung cancer, and suggest that targeting the Srx-Prx IV axis may provide novel effective strategies for cancer prevention and treatment.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A19.
Abstract A24: Resveratrol-induced and MTA1-associated miRNAs in prostate cancer prevention
Authors: Kai Li , Levenson Anait S.
Published: January 2011

Prostate cancer (PCa) remains one of the most frequently diagnosed cancers in men in Western countries. Since noticeable geographic variations have been observed in the incidence of PCa, studies have implicated a “Western” diet in the development of PCa. Because of this and the nature of PCa, which is typically diagnosed in the elderly population wth a relatively slower rate of growth and progression, chemoprevention through dietary compounds promises to be an effective approach for PCa. Resveratrol (Res) (3,5,4’-trihydroxy-trans-stilbene), a natural compound found in grapes, peanuts and berries, is one of the most promising diet-derived chemopreventive agent with potential chemotherapeutic capacities. There is growing evidence that Res may contribute to chromatin remodeling that are important in cancer progression. Metastasis-associated protein 1 (MTA1), which is overexpressed in many cancer, is a part of nucleosome remodeling and deacetylation (NuRD) complex that mediates posttranslational modifications of histones and nonhistone proteins resulting in transcriptional gene silencing. The complex also contains histone deacetylases 1 and 2 (HDAC1 and 2). MTA1/HDAC1 subunit plays an essential role in governing deacetylation of histones and other proteins. We recently demonstrated that Res down-regulated MTA1 protein levels in PCa cells, leading to destabilization of MTA1/HDAC1/NuRD complex thus allowing acetylation and activation of tumor suppressor p53. MTA1 silencing by RNA interference further sensitized PCa cells to Res-dependent p53 acetylation, transcriptional activation of p21 and Bax and apoptosis. To further understand Res-induced MTA1-associated epigenetic alterations, we analyzed MTA1-associated and Res-induced microRNAs expression changes using LNCaP cells expressing and silenced for MTA1. We found that expression of 13 miRNA was increase, and 17 miRNAs was decreased in cells silenced for MTA1 gene. In addition, 28 miRNAs were overexpresed, and 23 miRNAs were degreased under Res treatment. Among these miRNAs were some with well-characterized cancer association, such as let-7g, miR-16-2, miR-26a, miR-20b, miR-27a, miR-22, miR-34a, miR-92 and others. The predicted targets for the overlapping miRNAs are significantly enriched for protein-coding oncogenes and tumor suppressors. Our data indicate that MTA1-associated miRNAs are involved in Res-mediated anticancer and preventive effects in prostate cancer.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A24.
Abstract A27: STAT2 contributes to promotion of colorectal and skin carcinogenesis
Authors: Gamero Ana M. , Young Matthew R. , Mentor-Marcel Roycelynn , Bobe Gerd , Scarzello Anthony J. , Wise Jennifer , Colburn Nancy H.
Published: January 2011

This abstract is being presented as a short talk in Concurrent Session 4. A full abstract is printed in the Proffered Abstracts section (PR-02) of the Conference Proceedings.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A27.
Abstract A28: Expression of D4-GDI, a key regulator of Rho GTPases, in breast cancers
Authors: Rosado Leslie A. Rivera , Canales Jaime Rodriguez , Zhang Baolin
Published: January 2011

D4-GDI is a key regulator of Rho GTPases that have been implicated in many aspects of tumor progression. Despite its hematopoietic origin, we recently found D4-GDI to be expressed in human breast cancer cell lines. Targeted disruption of D4-GDI in a highly invasive breast cancer cell line inhibited tumor growth and experimental metastasis in a xenograft mouse model. The aim of this study was to investigate D4-GDI expression in primary breast tumors and to assess whether the expression levels of this protein could be associated with disease progression or other established clinical parameters. Following antibody validation, D4-GDI protein expression was assessed by tissue-microarray analysis of two human breast tissue arrays. Clinical parameters such as disease stages and/or hormone receptor status were available. Based on statistical analysis of the data we determined that D4-GDI levels were significantly higher in benign and early stage tumors when compared to normal breast tissues, which was followed by a dramatic decrease in high-grade malignant tumors and metastatic lesions to the lymph nodes. Breast cancer is thought to develop mostly from cells of luminal lineage; interestingly we observed that D4-GDI expression was almost exclusively found in the luminal cells of the ducts but not in the myoepithelial cells at the outer layer. In addition we found that alteration in D4-GDI expression levels resulted in changes in the expression of epithelial-to-mesenchymal transition (EMT) markers, a critical process for cancer progression. D4-GDI expression also appeared to be associated with the status of estrogen receptor (ER) whose deficiency is known to be linked with poor prognosis. These data support an important role for D4-GDI in tumorigenic transformation. Given its reverse relationship with ER status, D4-GDI levels might also provide additional information on the state of cancer progression as well as potential risk of metastasis in ER-negative patients.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A28.
Abstract A31: Bukhari molecular grading for squamous cell carcinoma and its correlation with pathologic prognostic factors.
Authors: Bukhari Mulazim Hussain , Iqbal Asifa , Majeed Muhammad M. , Jawad Amaila , Iqbal Sarah , Niazi Shahida , Khalil Muhammad Eyyaz
Published: January 2011

Background: Optimal patient management requires correct pathologic information regarding its prognostic value and definitive discrimination between the biological behavior of tumors. Traditional microscopic information often fails, especially when base on hematoxyllin and eosin methods. New grading system fills this void. The study was undertaken to determine the molecular grades of squamous cell carcinoma based on cumulative scores of histopathology, and proliferative activity and to see their correlation with pathological prognostic factors.

Materials and Methods: Scoring for histology, Ki-67 index, and p63 immunohistochemistry was done for 180 samples of squamous cell carcinoma with different histologic grades. Data regarding pathologic prognostic factors e.g., lymph node metastasis, local invasion, distance metastasis and recurrence was also collected for each case. Spearman correlation and Kendall's Tau-b test was used to assess association of molecular grading with pathologic prognostic factors. P <0.05 was considered statistically significant.

Results: Three grades (low, intermediate, and high) were determined by the sum of point values assigned to each 4 scores of histological differentiation, 5 p63 immunoreactivity scores and 4 scores of Ki-67. p63 scores were found to be related to the Ki-67 in the histological scoring of SCC. A significant correlation was found between the tumor grades and pathologic prognostic factors like stages (The molecular grades and the surgical stages are highly positively correlated, i.e. Spearman correlation = 0.721, p-value = 0.000) local invasion, lymph node involvement, distance metastasis (Kendall's Tau-b = 0.394; p-value = 0.00) and recurrence (Kendall's Tau — b = −0.966, p-value = 0.025).

Conclusion: Molecular features of the malignant cells were related to the pathological prognostic factors. New molecular grading is better in understanding the pathologic and clinical behavior of SCC at the molecular level.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A31.
Abstract A33: Identification of potential immunologic targets in mice and man that are overexpressed in colon adenomas and colorectal cancer
Authors: Broussard Elizabeth K. , Pritchard David K. , Lubet Ronald A. , Disis Mary L.
Published: January 2011

Multiple recent studies have demonstrated that colorectal cancer (CRC) is immunogenic and that host adaptive immunity (especially by CD4+ T cells) may play a role in inhibiting disease relapse or progression. We have shown that overexpressed tumor associated proteins, those abundant in the cancer state but expressed at basal levels in normal cells, can be immunogenic. The purpose of this study was to identify genes overexpressed in colorectal adenoma that maintain upregulation in CRC using publicly available microarray datasets in the NCBI Gene Expression Omnibus (GEO). Such genes may encode proteins that could be suitable as immunologic targets for a CRC vaccine. We identified 7 high quality datasets from 5 experiments (GSE 867, 4183, 1095, 5206, 15960) where human pre-malignant or cancerous tissue (3 adenoma and 4 CRC) was directly compared to normal colon. Inclusion criteria for the datasets included: commercial microarray platforms (Illumina or Affymetrix), primary tissue, normal colon expression included, data generated after 2005, and access to microarray raw data. We identified 100 genes that were at least 2-fold upregulated in both adenomas and CRC, relative to normal colon. We further characterized and ranked these genes by assigning numerical values to the following criteria: 1) strong expression in CRC as compared to normal colon at both the RNA and protein level, 2) evidence that the gene is biologically important in CRC initiation or progression, 3) limited gene expression in normal tissues, and 4) proven immunogenicity of the encoded protein. These analyses identified 83 candidate targets. We hypothesized that genes highly conserved across species would potentially have greater biologic relevance, so we analyzed relevant microarray studies in mouse CRC models (GSE 422, 784). We identified 226 murine genes upregulated in adenoma and CRC. Comparison of the human and rodent data sets revealed an overlap of 10 genes. We conclude that there are a limited number of genes upregulated in adenoma and CRC and conserved across disease in mouse and man. If these proteins are immunogenic, they may serve as novel immunologic targets to prevent the progression from normal colonic epithelium to adenoma or carcinoma.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A33.
Abstract A34: Cholesterol depletion in cell membrane induces apoptosis of oral cavity cancer cells
Authors: Kim So Yeon , Cho Chang Il , Kim Kyung-Su
Published: January 2011

Cell membrane cholesterol is not distributed evenly, but it mainly exists in a specific microdomain of cell membrane called lipid raft. The lipid rafts consist of cholesterol and glycosphingolipid, and are associated with the regulation of transmembrane receptors. Cholesterol depletion has been reported to bring structural disruption of the raft and functional change of associated receptors which leads to the induction of apoptosis in certain types of cells. In this study, the cell membrane cholesterol of oral cavity cancer cells such as SCC-15, SCC-25, and SCC-QLL1 cell line was depleted by treating with methyl β-cyclodextrin (MβCD), and the effect of cholesterol depletion on the induction of apoptosis was evaluated. Treating oral cavity cancer cells for 1 hour with 1% MβCD inhibited cell proliferation. The cholesterol analysis and the filipin fluorescence staining demonstrated that MβCD selectively depleted cholesterol in oral cavity cancer cells. Furthermore, flow cytometry, poly (ADP-ribose) polymerase (PARP) cleavage assay, ELISA cell death assay showed that this inhibition of cell proliferation was caused by apoptosis. To evaluate the relationship between Mitogen-activated protein kinases (MAPK) and this apoptosis, Western blot analysis of the oral cavity cancer cells treated with MβCD was performed using the antibodies of Phospho-Extracellular signal-regulated kinase (p-ERK), phospho-p38 MAPK, and phosho-Jun-N-terminal kinases (p-JNK). The activity of ERK, p38 MAPK, and JNK in each oral cavity cancer cells was changed after treating with MβCD. In conclusion, cholesterol depletion of cell membrane may be considered as one of treatment modalities for oral cavity cancer, but further studies on its mechanism will be needed.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A34.
Abstract A36: Topoisomerase II-dependent apoptosis induced by dietary isothiocyanates
Authors: Lin Ren-Kuo , Zhou Nai , Tsai Yuan-Chin , Lu Chang-Hsieh , Lyu Lisa Y. , Liu Leroy F.
Published: January 2011

Cruciferous vegetables, such as broccoli and watercress, have been studied extensively for their chemopreventive activities in animal models. It has been demonstrated that the thiol-reactive isothiocyanates (ITCs) are primarily responsible for their chemopreventive activity. While ITCs are known to induce Phase II enzymes and hence detoxification of certain carcinogens to prevent initiation of carcinogenesis, they also exhibit antitumor activity at a post-initiation phase, suggesting their additional role(s) in cancer prevention. In vitro studies have demonstrated that ITCs induce apoptosis which could be linked to their chemopreventive activity in the post-initiation phase. A number of studies have suggested that IKK inhibition, NF-κB suppression and/or STAT3 down-regulation may contribute to ITC-induced apoptosis. Here, we provide evidence that topoisomerase II (Top2) is involved in ITC-induced apoptosis in cultured tumor cells: (1) BITC (benzyl isothiocyanate) and PEITC (phenethyl isothiocyanate) induced much reduced apoptosis in HL-60 cells and T-antigen transformed MEFs transfected with Top2α siRNA. (2) Similarly, the induction of the DSB signal, γ-H2AX, was also reduced in HL-60 cells transfected with Top2α siRNA. (3) BITC and PEITC induced Top2-mediated DNA damage in vitro through the formation of topoisomerase II-DNA covalent complexes. Together, these results suggest a possible role of Top2 in ITC-induced cell death, presumably through the formation of topoisomerase II-DNA cleavage complexes.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A36.
Abstract A37: A study on the mechanism of chemoprevention by celecoxib and fish oil in experimental mammary carcinogenesis
Authors: Agnihotri Navneet , Negi Anjana K. , Sarotra Pooja , Kansal Shevali , Sharma Gayatri
Published: January 2011

Background: Cyclooxygenase (COX)-2 inhibitor, celecoxib and n-3 poly unsaturated fatty acid (PUFA) rich fish oil has been reported to have a synergistic chemopreventive effect on colon and breast cancer in animal models and this effect may be mediated through alteration in apoptosis and cell cycle. Therefore, the present study was designed to understand the mechanism of action of this combinatorial strategy in 7,12-Dimethylbenz(a) anthracene (DMBA) induced mammary carcinogenesis.

Study Design: Female Wistar rats were distributed into six groups: group-1 (vehicle treated), group-2 (DMBA treated), group-3 (20mg/kg body weight celecoxib + DMBA), group-4 (0.5 ml fish oil + DMBA), group-5 (20 mg/kg body weight celecoxib+0.5 ml fish oil) and group-6 (20 mg/kg body weight celecoxib+0.5 ml fish oil + DMBA). The animals were pretreated with the respective dose regimens orally for one week prior to the DMBA (15mg) dose. The animals were subsequently maintained for 90 days and then sacrificed. The levels of reactive oxygen species (ROS) by 2’,7’-dichlorofluorescein diacetate (DCFH-DA), intracellular Ca2+ by fluo-3-penta-acetoxymethylester (fluo-3-AM) dye, p53 by monoclonal antibody and mitochondrial membrane potential (MMP) by 5,5,6,6-tetrachloro-1,1,3,3-tetraethylbenzamidazolo-carbocyanin iodide (JC-1) dye were estimated in isolated mammary epithelial cells.

Results: A significant increase in ROS, intracellular calcium and p53 levels and a decrease in MMP were observed in DMBA treated rats as compared to control animals.

There was a significant decrease in p53, intracellular calcium and ROS generation on pretreatment with either celecoxib, fish oil or combination dosage of celecoxib and fish oil in DMBA treated animals with respect to only DMBA treated animals (group 2) with a comparatively marked alteration in combination dose regimen. However, an increase in MMP was observed in fish oil and the combination dosage regimen with respect to DMBA treated animals. Fish oil treatment in comparison to celecoxib in DMBA treated animals led to a significant increase in calcium, ROS and MMP levels. To conclude a synergistic effect of celecoxib and fish oil was observed in intracellular calcium, ROS and p53 levels in DMBA treated animals which may be responsible for the better chemopreventive efficacy of the combinatorial regimen.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A37.
Abstract A38: Chemopreventive effect of different ratios of fish oil and corn oil in experimental colon carcinogenesis
Authors: Sarotra Pooja , Kansal Shevali , Sandhir Rajat , Agnihotri Navneet
Published: January 2011

Aim: The present study was designed to study the chemopreventive effect of different ratios of n-3 PUFA rich fish oil and n-6 PUFA rich corn oil on prognostic markers, DNA damage and cell cycle phases in experimentally induced colon carcinoma.

Methods: Male Wistar rats were divided into control, dimethylhydrazine dihydrochloride (DMH) treated, FO+CO(1:1)+DMH and FO+CO(2.5:1)+DMH. All the groups, except control received a weekly injection of DMH for 4 weeks. The animals were sacrificed either 48 hrs later (initiation phase) or kept for 16 weeks (post initiation phase). The chemopreventive efficacy was evaluated by analyzing the regression of preneoplastic lesions, total sialic acid (TSA), lipid associated sialic acid (LASA). To study the underlying mechanisms DNA damage, distribution of cells in various phases of cell cycle, cyclin D1 and p53 levels were assessed in the isolated colonocytes.

Results: The animals treated with DMH in the initiation phase and post initiation phase studies showed increase in Multiple plaque lesions (MPL), total sialic acid (TSA), lipid associated sialic acid (LASA), DNA damage and cell proliferation with increased percentage of cells in G2M and S phase. However, levels of p53 and cyclin D 1 were not significantly altered in the initiation phase while levels were significantly elevated in the post initiation phase study on treatment with DMH.

The FO+CO(1:1)+DMH treatment in the initiation phase and post initiation phase led to a decrease in the MPL, DNA damage, TSA, LASA as compared to the control and DMH treated group. The cells were arrested in the G1 phase with a decrease in G2M and S phase. The levels of p53 and cyclin D1 were not significantly altered while a decrease in the levels was observed in the post initiation phase as compared to the DMH treated animals.

Treatment with FO+CO(2.5:1)+DMH in the initiation phase study and post initiation phase study led to a decrease in the MPL, TSA, LASA and DNA damage as compared to the DMH treated animals. The levels of p53 and cyclin D1 remain unaltered on treatment with FO+CO(2.5:1)+DMH in the initiation phase study. However a decrease was observed in the post initiation phase as compared to the DMH treated animals. The cells were arrested in the G1 phase in the initiation phase and revert to normal in the post initiation phase showing the protective effect. There was more protective effect in the FO+CO(2.5:1)+DMH treated animals as compared to the FO+CO(1:1)+DMH treated animals in the initiation phase and the post initiation phase showing the dose and time dependent effect of n-3 PUFAs.

Conclusion: The results of the present study suggest that fish oil and corn oil in the ration of 2.5;1 is more effective in chemoprevention of experimental colon carcinogenesis.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A38.
Abstract A4: Protection against radiation-induced carcinogenesis
Authors: Mitchell James B. , Anver Miriam , Sowers Anastasia , Figueroa Maria , Thetford Angela , Krishna Murali C. , Albert Paul S. , Cook John A.
Published: January 2011

The rationale of this study stems from the concern of radiation-induced second malignancies after a course of definitive radiation therapy or the possibility of a terrorist-mediated nuclear attack resulting in large populations of people exposed to non-lethal radiation doses, which would substantially increase the risk for cancer induction post-exposure. Currently, there are no safe and effective interventions to reduce this risk to humans. Previous studies have shown that chronic administration of Tempol (nitroxide antioxidant) in the diet of mice results in decreased weight and spontaneous tumorigenesis, and increased tumor latency (Mitchell JB, et al., Free Radic Biol Med 34:93-102, 2003). In the current study we tested the hypothesis that Tempol (TP) administered in the diet of mice would reduce radiation-induced cancer when given after the radiation exposure. Total body radiation (3 Gy) was administered to female C3H and CBA mice. Along with various control groups, immediately after radiation one group of animals from each strain was placed on a TP diet. Food consumption and animal weights were monitored throughout the study. Animals were followed for their entire lifespan (>1300 mice). The endpoint for the study was tumor formation or until the animal reached a humane endpoint at which time the animal was euthanized and evaluated for the presence of tumor (pathology evaluated on all animals). TP food supplementation after radiation: a) did not alter food consumption compared to animals on a control food diet, b) compared to animals on control food diet, the TP diet resulted in decreased weights in both mouse strains (40% for C3H and 20% for CBA), and c) TP food supplementation post-radiation significantly enhanced the survival of both mouse stains. Median survival values for 0 Gy, 3 Gy, 0 Gy TP, and 3 Gy TP for C3H mice was 706, 434, 764, and 670 days, respectively. For CBA mice median survival values for 0 Gy, 3 Gy, 0 Gy TP, and 3 Gy TP for C3H mice was 901, 660, 939, and 782 days, respectively. The incidence of hematopoietic neoplasms (predominantly lymphomas) was significantly reduced in both mouse strains by TP treatment and both the onset and incidence of solid neoplasms was significantly reduced in CBA mice treated with TP. These results encourage more research on nitroxide-based antioxidants in the chemoprevention of cancer to elucidate the mechanism(s) involved.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A4.
Abstract A52: Koetjapic acid suppresses angiogenesis causing inhibition in VEGF expression
Authors: Shah Amin Malik , Majid Abdul , Nassar Zeyad D. , Aisheh Abdelrahim A. , Alrokayyan Salman A. , Abu-Salah Khalid M.
Published: January 2011

Koetjapic acid is a naturally occurring ichthyotoxic compound which can be isolated from the stem bark of Sandricum keotjape. This is a large tree species that can be found widely in Malaysia and other tropical countries in Southeast Asia. In our studies, we found koetjapic acid to be strongly antiangiogenic causing significant inhibition in endothelial tube formation. The compound inhibited VEGFA expression and caused retardation in cell migration. Keotjapic acid also suppressed the activity of Hif-1a and up regulates TGFβ and NFκB activity. This suggests the potential use of Keotjapic acid to target ailments that is angiogenesis dependent.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A52.
Abstract A53: Antiangiogenic activity of GER, a derivative of sweet leaf tea extract, is mediated by the downregulation of bFGF and VEGF
Authors: Yang Peiying , Cartwright Carrie , Liu Dong , Liu Zhijun
Published: January 2011

Mounting evidence indicates that angiogenesis is essential for the proliferation and survival of number of malignant diseases, thus inhibition of angiogenesis might be an effective therapeutic strategy. Antiangiogenic agent that targets both bFGF and VEGF (VEGFR) are considered to be effective adjuncts to the treatment of solid tumors or cancer preventive. Chinese sweet leaf tea, a hot water extract of Rubus suavissimus S. Lee (Rosaceae) (RUS) has been reported to have antiangiogenic activities evidenced by its ability to inhibit the angiogenic initiation and growth of human placental vein tissue (Liu et al., Phytother, Res. 20: 806-813, 2006) and experimental corneal neovascularization (Hakan, O.F., et al, Pharmaceu. Biol. 45: 44-47, 2007). We reported that this particular extract has the ability to inhibit the endothelial tubule formation, migration, and VEGF (VEGFR) of the HUVEC cells (Proc. Am. Assoc. Cancer Res, 1432, 2009). Here we investigated the anti-angiogenic activity of GER, a combination of gallic acid, ellagic acid, and rubusoside purified from the RUS and the relevant molecular mechanisms using HUVEC cells. Our preliminary data demonstrated that GER (5 to 25 µg/ml) markedly inhibited migration of HUVEC cells compared to the vehicle control. This inhibitory effect was concentration-dependent. At a similar concentration, the endothelial tubule formation was almost completely inhibited. When HUVEC cells were treated with GER (5 to 20 µg/ml), the expression of both bFGF and VEGF were markedly inhibited even at the lowest starting concentration. These inhibitory effects were also concentration-dependent. To further confirm the involvement of VEGF pathway in GER-induced anti-angiogenic activity, the protein level of tyrosine kinase receptor VEGFR2 (Flk-1/KDR) was examined. Intriguingly, the expression of Flk-1 was significantly suppressed in HUVEC cells treated with GER (40 µg/ml) by 54.1% ± 2.3% in comparison to that of vehicle control. In contrast, VEGFR2 kinase activity and protein levels of VEGFR1 remained unchanged compared to that of the vehicle control. These results suggest that GER derived from the sweet leaf tea extract may be completely responsible for the observed anti-angiogenic effect of the sweet leaf tea reported previously by down-regulating proangiogenic factors bFGF and VEGF. The chemopreventive effect of GER and its parent extract RUS on the development of human pancreatic carcinoma (L3.6pl cells) in mouse orthotopic model is currently under investigation and will be reported. This study was supported by NIH grant 1R21 AT002882-01A2.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A53.
Abstract A57: Breast adipocytes bioactivate Vitamin D3 and regulate hormone-induced epithelial cell growth
Authors: Zinser Glendon M. , Kashinkunti Soumya , Niehaus Matt
Published: January 2011

Vitamin D3, a nutritionally modulated hormone, participates as a negative growth regulator of mammary gland development and transformation. However, the mechanism behind breast specific vitamin D3 synthesis, metabolism, and signaling to maintain glandular homeostasis and inhibit the onset of mammary transformation remains unknown. Our objective was to test the concept that vitamin D3 signaling in mammary adipose tissue contributes to the negative growth regulation of mammary epithelial cells. We hypothesized that the mammary adipose tissue bioactivates 25-hydroxyvitamin D3 [25(OH)D3] to the active metabolite, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], and induces adipocyte Vitamin D3 Receptor (VDR) signaling along with paracrine secretion of 1,25(OH)2D3 to surrounding mammary epithelial cells to regulate growth of normal and transformed breast epithelial cells. We utilized mammary glands from VDR knockout (KO) and wild type (WT) mice for various procedures including ex vivo co-cultures with mammary epithelium and adipocytes, gene and protein expression assays, immunohistochemistry, and whole mount analysis. We discovered that breast adipocytes express essential signaling components of the vitamin D3 endocrine system and have the ability to bioactivate 25(OH)D3 to 1,25(OH)2D3 inducing mammary specific vitamin D3-responsive gene expression. Breast adipocytes likely participate to maintain localized vitamin D3 homeostasis and contribute to 1,25(OH)2D3-induced growth regulation of mammary epithelial cells in response to various hormonal stimulations, modulating mammary development and differentiation. Thus, our work suggests that breast adipose tissue serves as a vital endocrine mediator of Vitamin D3 signaling and offers a possible mechanism by which elevated 25(OH)D3 serum concentrations reduce the susceptibility to breast cancer.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A57.
Abstract A58: Activation of diverse signaling pathways in pancreatic cancer revealed by phosphoproteomics
Authors: Kim Min-Sik , Kuppireddy Sarada Vineela , Zhong Jun , Jacob Harrys KC , Marimuthu Arivusudar , Kashyap Manoj Kumar , Pandey Akhilesh
Published: January 2011

Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States. Based on genomic studies, a number of genes that have somatic mutations including CDKN2A, SMAD4, TP53 and KRAS have been identified in pancreatic cancers. Recently, a comprehensive genomic analysis was performed in a panel of 14 primary pancreatic cancer cell lines and 10 xenografts, in which ∼1,500 somatic alterations were identified and a core set of 12 signaling pathways were defined.

In this study, we characterized the 14 primary pancreatic cancer cell lines whose genomes have been sequenced. From Western blots using anti-phosphotyrosine antibodies, we observed a heterogeneous pattern of tyrosine phosphorylation in these cell lines, indicating that different tyrosine kinases were likely activated in different cells. Phosphotyrosine-containing peptides were enriched by immunoprecipitation by anti-phosphotyrosine antibodies. The enriched phosphopeptides were analyzed on a high resolution Fourier transform mass spectrometer coupled to nanoflow reverse phase liquid chromatography.

Our preliminary data indicates that the approach used in this study is suitable for the global profiling of tyrosine kinase pathways that are abnormally activated in pancreatic cancers. For example, lymphocyte-specific protein tyrosine kinase and spleen tyrosine kinase were observed to be activated in one of pancreatic cancer cell lines (Panc 8.13), while insulin receptor was activated in different cell lines (Panc 198).

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A58.
Abstract A59: Prospective analysis of the association between use of statins or other lipid-lowering agents and colorectal cancer risk
Authors: Simon Michael S. , Rosenberg Carol A. , Rodabough Rebecca A. , Greenland Philip , Ockene Ira S. , Hemant Roy K. , Lane Dorothy S. , Cauley Jane A. , Khandekar Janardan D.
Published: January 2011

Background: Experimental and epidemiologic data suggest that 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) have antitumor activity against colorectal cancer (CRC). We utilized data from the population-based Women's Health Initiative (WHI) cohort to assess whether statins are associated with a decreased risk of CRC.

Methods: The study population included 159,219 postmenopausal women ages 50-79 at baseline, in which 2,000 cases of CRC were identified over an average of 10.7 (2.9) years of follow-up. All cases of CRC were confirmed by review of medical records and pathology reports. Participants were asked to bring all current medications to their screening interviews and clinic staff entered information on statin use and other lipid lowering medications into the WHI database. Self- and interviewer-administered questionnaires were used to collect information on other CRC risk factors. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Analyses investigated the association of any statin use, type of statin, statin potency, and duration of use with CRC. Statistical tests were two-sided.

Results: Statins were used by 12,030 (7.6%) women in the cohort. The annualized rate of CRC was 0.13% among statin users and 0.12% among nonusers. The multivariable adjusted HR for statin users compared with nonusers was 0.99 (95% CI=0.83 to 1.20, p=0.95). There was no trend in risk of CRC by duration of statin use, with HR = 0.91 (95% CI=0.66 to 1.27) for < 1 years of use, HR = 1.28 (95% CI=0.97 to 1.68) for 1- < 3 years of use, and HR =0.79 (95% CI=0.56 to 1.11) for > 3 years of use. There was no relationship between type of statin use, statin potency (low, medium and high), or use of other lipid-lowering medications and CRC risk. In addition there was no relationship between statin use and tumor location (proximal, distal and rectal), or clinical features (tumor stage, grade or histology).

Conclusions: Statin use was not associated with a decrease in CRC risk in the WHI cohort.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A59.
Abstract A65: Gene-based test for lung cancer risk motivates smoking cessation in randomly selected smokers
Authors: Hopkins Raewyn J. , Young Robert P. , Hay Bryan A. , Gamble Gregory D.
Published: January 2011

Personalized risk assessment has been successfully used in coronary heart disease prevention to motivate lifestyle change and target drug therapy. In the Tension, Trigger and Treatment (3Ts) paradigm of smoking cessation, smokers quit smoking when the perceived harms outweigh benefits (or when motivational tension outweighs optimistic bias). Using a gene-based test for lung cancer risk, recently validated in a prospective study, we examined the effect of risk assessment on smoker's attitudes and actions to quitting. In this pilot study, 28 smokers were randomly recruited from a hospital database (eligibility: ≥40 years old, current smoker, and 20+ pack year smoking history). Through a telephone questionnaire, baseline smoking history and recent quit attempts were documented. Smokers were also offered a gene-based risk test for lung cancer risk. 25 (90%) accepted and were followed. On visit 1, smokers were counseled, consented and a cheek swab was taken for genotyping. On visit 2, the lung cancer risk test result was given along with materials on smoking cessation services and medications.

Based on a telephone questionnaire at 6 months after genetic testing (n=25) we found the following; 32% had quit smoking while 48% had reduced their smoking consumption (overall 80% had taken positive steps toward reducing smoking), 48% had used a smoking cessation service or product and only 4% of smokers appeared less committed to quitting. Quit rates were comparable in moderate- and high-risk groups.

We conclude from this pilot study that personalized risk assessment using a gene-based test of lung cancer susceptibility appears to confer a positive effect on quitting smoking. The quit rates achieved in this study occurred in randomly selected smokers and compares favorably with other approaches. We suggest that the risk test provides a teachable moment and enhances motivational tension towards quitting.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A65.
Abstract A67: Phase IIA trial testing erlotinib as an intervention against intraductal papillary mucinous neoplasms
Authors: Lipkin Steven M. , Lee John , Imagawa David , Zell Jason , Wong Vanessa , Gonzalez Rachel , Della'Zanna Gary , Richmond Ellen , Rodriguez Luz , Meyskens Frank
Published: January 2011

Intraductal papillary mucinous neoplasms (IPMNs) account for about 7% of clinically diagnosed pancreatic neoplasm and up to 50% of all incidentally detected pancreatic cysts. Described by Oshi et al in 1982, the incidence of these mucin-producing epithelial tumors of the exocrine pancreas has been increasing. Furthermore, IPMNs are thought to be direct precursors of pancreatic ductal carcinoma (PDA), which is among the most lethal human cancers. Many of the IPMNs are detected occur in nonsurgical candidates. Those surgically resected, a significant proportion develops PDA in the pancreatic remnant and die of disseminated disease. There is currently no chemotherapy specifically approved for treating IPMNs. Erlotinib (Tarceva, OSI-774) is an anti epidermal growth factor receptor (EGFR) orally active antitumor agent for treatment of solid tumors that is used in combination with chemotherapy to treat pancreatic adenocarcinoma.

A single arm, presurgical phase IIa trial using 100mg erlotinib in IPMNs patients (7-28 days prior to surgery) was conducted. Pre and post-erlotinib IPMN tissues were compared for a reduction in the EGF regulated biomarker Mucin 5AC (MUC 5AC) as the primary outcome. Secondary outcomes included clinical regression of IPMNs and quantification of the concentration of erlotinib in pancreatic tissue. Six IPMN patients were enrolled and pancreatic surgical specimens consistently showed decreased MUC5AC with erlotinib treatment. Additionally, one patient had a clinical complete response by CT criteria. No unanticipated safety issues were observed in trial participants. Overall, these preliminary results suggest erlotinib and other EGFR antagonists should be examined further for anti-IPMN activity.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A67.
Abstract A68: Randomized presurgical trial of finasteride vs. flutamide vs. placebo in prostate cancer
Authors: Zanardi Silvia , Maffezzini Massimo , Puntoni Matteo , Montironi Rodolfo , Johansson Harriet , Campora Sara , Vagge Alessandra , Rondanina Gabriella , Bandelloni Roberto , Turbino Laura , Mori Marco , Hurle Rodolfo , Decobelli Ottavio , Carmignani Giorgio , Santinelli Alfredo , Mazzucchelli Roberta , Bartels Peter H. , DeCensi Andrea
Published: January 2011

This abstract is being presented as a short talk in Concurrent Session 5. A full abstract is printed in the Proffered Abstracts section (PR-03) of the Conference Proceedings.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A68.
Abstract A73: Randomized placebo-controlled trial of pioglitazone for oral premalignant lesions: A cross-consortium collaborative study in progress
Authors: Boyle Jay O. , Ondrey Frank G. , Brown Powel H. , Bailey Howard H. , Kim KyungMann , El-Naggar Adel K. , Szabo Eva M.
Published: January 2011

This abstract is being presented as a short talk in Concurrent Session 14. A full abstract is printed in the Proffered Abstracts section (PR-10) of the Conference Proceedings.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A73.
Abstract A75: Nonsteroidal anti-inflammatory drugs (NSAIDs) and colorectal cancer risk in the National Institutes of Health-AARP Diet and Health Study
Authors: Ruder Elizabeth H. , Laiyemo Adeyinka O. , Graubard Barry I. , Hollenbeck Albert R. , Schatzkin Arthur , Cross Amanda J.
Published: January 2011

Background and Aims: Prolonged nonsteroidal anti-inflammatory drug (NSAID) use has been associated with lower colorectal cancer risk; however, little is known about the association of NSAID use within colorectal subsites or among individuals with a family history of colon cancer. This study assessed NSAID use and colorectal adenocarcinoma by subsite, including subanalysis of individuals with a family history of colon cancer.

Methods: Using Cox proportional hazard regression, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between NSAID use and colorectal cancer incidence among 301,240 participants; of whom 26,994 individuals reported having a first degree relative with history of colon cancer. We accrued 3,894 colorectal cancer cases during 10 years of follow-up; 372 cases had a first degree relative with colon cancer.

Results: Use of aspirin or non-aspirin NSAIDs (yes versus no) reduced colorectal cancer risk (HR=0.91, 95% CI: 0.85, 0.98; HR=0.82, 95% CI: 0.77, 0.87, respectively); these risks were lowered with increasing frequency of use (HR=0.86, 95% CI: 0.79, 0.94; HR=0.71, 95% CI: 0.63, 0.80 for daily use compared to non-users of aspirin or non-aspirin NSAIDs, respectively). Participants with a first degree relative with colon cancer who used non-aspirin NSAIDs daily had reduced colon cancer risk specifically (HR: 0.49, 95% CI: 0.29, 0.82).

Conclusions: NSAID use reduced colorectal cancer risk; the magnitude of this association varied with NSAID type and tumor location. Daily non-aspirin NSAID use was associated with a 50% lower risk of colon cancer in those with a first degree relative with this malignancy.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):A75.