bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract PR16: Important bidirectional function in the Notch-Delta signaling in pancreatic carcinogenesis and metastasis
Authors: Mazur Pawel K. , Lubeseder-Martellato Clara , Grüner Barbara M. , Kaznowska Ewa , Sipos Bence , de Angelis Martin Hrabé , Schmid Roland M. , Sage Julien , Siveke Jens T.
Published: June 2012

Pancreatic cancer is a dismal disease with a median survival of less than 6 months. Its high mortality is due to aggressive development and early lymphatic and hematogenic dissemination. Notch signaling has been shown to regulate pancreatic carcinogenesis; however, a specific role of the Notch ligands has not been extensively studied thus far. Here we investigate the role of Delta1 ligand in pancreatic carcinogenesis and metastasis.

Our study using a reporter mouse indicates that Delta1 is mainly expressed in centroacinar and ductal cells as well as in pancreatic intraepithelial neoplasia (PanIN) lesions. Expression in those vulnerable cell compartments and preneoplastic lesions imply relevance for carcinogenesis. Moreover, during cancer development, Delta1 shows the highest relative increase in expression among all Notch ligands suggesting it predominantly functions in Notch pathway activation. Its potentially important role in tumorigenesis was investigated using a KrasG12D-driven pancreatic carcinogenesis mouse model inbreed with a Delta1LacZ/+ haploinsufficient mouse. In KrasG12D;Delta1LacZ/+ mice we observed a delay in PanIN progression and increased development of mucinous cystic neoplasia. Obtained results support our hypothesis. Moreover, in vitro data indicates that Delta1 is critical for Notch2 activation that directly regulates pancreatic cancer progression via cMyc induction.

We also analyzed expression and role of the intracellular domain of Delta1 (Delta1-IC). We found that Delta1-IC is accumulated in pancreatic cancer distal metastasis. Our investigations strongly suggest that Delta1-IC can enhance metastatic potential by interaction with transducers of TGFβ signaling: Smad3 and Smad4. We found that Delta1-IC by co-binding to Smad3-regulated promoter proteins can increase TGFβ-induced transcriptional changes in the cell leading to increased cellular motility and EMT capacity. We establish that nuclear accumulation of Delta1-IC correlates with patients' poor outcome and presents of metastasis as well as tumor stage. Our investigation proofs the importance of Notch signaling and points to its bidirectional function in pancreas carcinogenesis and metastasis.

This abstract is also presented as Poster A62.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr PR16.
Abstract PR4: Regulation of the Fanconi anemia pathway by a SUMO-like delivery network
Authors: Yang Kailin , Moldovan George-Lucian , Vinciguerra Patrizia , Murai Junko , Takeda Shunichi , D'Andrea Alan D.
Published: June 2012

Objective: The USP1/UAF1 complex is a critical regulator of the FA pathway. The USP1/UAF1 complex deubiquitinates the Fanconi Anemia proteins, FANCD2/FANCI, and promotes homologous recombination and DNA crosslink repair. USP1/UAF1 also deubiquitinates PCNA-Ub, a key player in translesion DNA synthesis. This step requires the PCNA interacting protein, hELG1. The goal of our study is to identify the molecular mechanism of USP1/UAF1 complex targeting to the FANCD2-Ub/FANCI-Ub heterodimer and tothePCNA-Ub/hELG1 complex.

Methods: Using bioinformatics, we identified a tandem repeat of SUMO-like domains (SLD) in the C-terminus of UAF1 (SLD1 and SLD2). A SLD sequence is a domain of approximately 100 amino acids with significant sequence identity and homology to the small ubiquitin-like modifier (SUMO). We tested the function of a mutant form of UAF1 lacking the SLD2 domain. Interestingly, this mutant UAF1 protein bound and stimulated the deubiquitinating activity of USP1 but failed to complement UAF1 knockout DT40 cells. We then discovered a SUMO-like-domain interacting motif (SIM) on both FANCI and hELG1. We therefore investigated the functional importance of the SLD-SIM interaction in regulating the Fanconi anemia pathway.

Results: The SLD2 domain of UAF1 is dispensable for activating USP1 in vitro. However, complementation analyses using UAF1 knockout DT40 cells showed that the SLD2 is critical for the deubiquitination of USP1 substrates in vivo and for homologous recombination. We demonstrated that the SLD2 domain of UAF1 binds directly to the SIM sequence on FANCI and hELG1, and thereby regulates the deubiquitination of FANCD2-Ub and PCNA-Ub respectively. Disruption of these SLD-SIM interactions blocked the deubiquitination of FANCD2-Ub and/or PCNA-Ub, rendering cells DNA repair deficient. We also modeled the 3-D structure of SLD2 and identified critical residues involved in SLD-SIM interaction.

Conclusions: Our study demonstrates that unique SLD-SIM interactions mediate the targeting of the USP1/UAF1 deubiquitinating complex to its monoubiquitinated substrates, FANCD2/FANCI and hELG1/PCNA, and thereby coordinate homologous recombination. This is a novel mechanism of DNA repair regulation, and it may have relevance to other DNA repair pathways.

The SLD-SIM interaction sites are potential drug target sites for agonists or antagonists of the FA pathway. They may be useful in screening drugs for the treatment of FA patients and cancer patients from the general (non-FA) population.

This abstract is also presented as Poster B38.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr PR4.
Abstract PR8: From prediction to prognosis and therapeutics: The power of breast cancer transcriptional networks
Authors: Zhang Bin , Derry Jonathan , Schadt Eric , Friend Stephen , Zhu Jun , Dai Xudong , Wang Zhi , Meng Fanyan , Tran Linh , Zhang Zhan , Guinney Justin , Clurman Bruce , Wu Guojun
Published: June 2012

Complex human diseases such as cancer are driven by interacting networks at molecular, cellular and environmental levels. Increasingly available large-scale high-throughput genetic and genomic data makes it possible to reconstruct predictive molecular networks that characterize diseases and indentify causal drivers for therapeutic intervention. Here we present an integrative network approach to analyze multiple large scale gene expression datasets in breast cancer.

We compiled four large-scale breast cancer gene expression datasets (van't Veer, Dai et al. 2002; Miller, Smeds et al. 2005; Wang, Klijn et al. 2005; Sotiriou, Wirapati et al. 2006). Gene coexpression networks were first constructed on individual datasets to derive gene modules comprised of highly interconnected genes. Gene modules significantly conserved in multiple co-expression networks were then grouped into consensus modules. Meanwhile, Bayesian networks (BN) were also constructed from the individual datasets and combined by union of directed links to form a super BN. The consensus gene modules were used to partition the combined BN into a number of functional regions to derive module based regulatory subnetwork for which key regulators were then identified through key driver analysis. Novel pathways such as ARFs pathways were uncovered to be essential for breast cancer progression and subsequently validated. The predicted novel drivers were systematically validated through a large number of siRNA experiments. The driver genes are not only predictive of survival time and chemotherapy response but also effective in elucidating drug mechanisms. An FDA approved anti-hypertensive drug, predicted by our integrative network analysis to be effective on breast cancer, dramatically and selectively inhibits proliferation of breast cancer cells through inhibition of cell cycle activity while keeping the majority of normal cells alive.

Such an integrative network approach and the findings will have significant impact on breast cancer research and drug development, while more broadly facilitating study and treatment of complex human diseases.

This abstract is also presented as Poster B21.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr PR8.
Abstract A104: Leptin and leptin receptor genes in relation to premenopausal breast cancer incidence and grade in Caucasian women
Authors: Gu Fangyi , Kraft Peter , Rice Megan , Michels Karin B.
Published: June 2012

Background: Body mass is inversely related to breast cancer risk among premenopausal women. Leptin, an essential cytokine regulating food intake, energy expenditure, glucose and fat metabolism may be part of the mechanistic pathway.

Methods: We investigated 50 tagging and candidate SNPs in the leptin (LEP) and leptin receptor (LEPR) genes, for associations with premenopausal breast cancer incidence using 405 cases and 810 controls nested within the Nurses' Health Study II. We also examined associations between these SNPs and circulating leptin (among 910 women) and breast cancer grade (among 267 patients). Permutation tests were performed to adjust for multiple testing.

Results: We did not detect a significant association between SNPs in the LEP or LEPR gene and either breast cancer incidence or plasma leptin levels. However, among cases, 14 SNPs of the LEPR gene were significantly associated with cancer grade, and rs1137101 (Q223R) survived multiple testing adjustment (adjusted p=0.04). The G carriers of rs1137101 were more likely to have poorly differentiated than well differentiated cancers. Conclusions: Our data suggest that common genetic variation in the LEP or LEPR gene has no strong association with premenopausal breast cancer risk. The LEPR gene might be associated with breast cancer grade.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A104.
Abstract A115: Natural history of HPV in cervical tumors: Identification of genotypes from formalin-fixed cervical tissues
Authors: Bukhari Mulazim Hussain , Saba Kanwal , Zainab Maidah , Ghayyor Ahmad , Qadri Ishtiaq
Published: June 2012

Background: Since the identification of HPV as the necessary cause of cervical cancer, knowledge of its natural history for cervical infection; genotypes, load and form, is essential to prevent and predict cervical carcinoma. A cross sectional study was conducted to see the natural history and genotypes of HPV in cervical neoplastic lesions.

Materials and Methods: Two diagnostic modalities, IHC and PCR, were performed on 102 diagnosed cases of cervical premalignant and malignant lesions (Cervical Neoplastic Lesions: CNL) and lesions by histopathology.

Results: Out of the102 cases there were 12, 44,40 and 6 cases of Squamous cell Papilloma(SCP), Squamous Cell Dysplasia(CD), Squamous Cell Carcinoma(SCC) and Adenocarcinoma(ADC) respectively. There were 82 CNL, which showed positive HPV reaction on IHC while 88 CNL showed presence of HPV (56/88:64% HPV-18 and 32/88:36% HPV-18) on PCR. There was significant association between the presence of HPV and p53 mutation among different CNL. There was no statistical difference in lesions with respect to positivity of HPV and P53 suggesting that the expression of this suppressor gene was affected by the presence of the HPV genome, p-value>0.05.IHC scoring of CNL was not significantly affected with HPV infection (p-value>0.05). The overall sensitivity, Specificity and accuracy of IHC against PCR was 93%,70,89% merits and demerits of each modality has also been given in detailed. The major mode of infection of HPV-16 was host nuclear integration (p:0.000) with different variant with predominant E-350G genotype(p:0.000). High Viral load was seen in infected cervical tissues.

Conclusion: HPV-18&16 were detected;E-350 G genotype was most common form while predominant way of infection was host nuclear integration of HPV. The etiological involvement of HPV in the development of CNL was found because of high viral load and significant association with p53 protein expression with HPV infection.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A115.
Abstract A12: Validity of aberrant crypt foci using as a surrogate biomarker for colorectal cancer
Authors: Sakai Eiji , Takahashi Hirokazu , Nakajima Atsushi
Published: June 2012

Introduction: Aberrant crypt foci (ACF) are considered to be useful as surrogate biomarker for colorectal cancer (CRC), but the biological significance of ACF remains controversial. We attempted to investigate the relationship between the presence of ACF and human colorectal carcinogenesis using a relatively large sample size.

Methods: We performed high-magnification chromoscopic colonoscopy to identify ACF in 861 subjects undergoing a diagnostic endoscopy at the Yokohama City University Hospital. The present study compared the prevalence and number of ACF in three subject groups (normal subjects, adenoma cases, and CRC cases). The correlations between the demographic and behavioral characteristics of the subjects and the prevalence of ACF were also assessed.

Results: The prevalence of ACF was 64%, 88% and 95%, and the mean number of ACF was 3.6, 6.2 and 10.1, in normal subjects, adenoma cases, and CRC cases, respectively. Older age and men had increased prevalence and number of ACF. When differences in the prevalence and number of ACF among age- and sex-stratified subject groups were examined, significant stepwise increments from normal subjects to adenoma cases to CRC cases were apparent (P<0.001). Moreover, an age- and sex-adjusted multiple logistic regression analysis revealed that smoking and alcohol habits had a synergistic effect, increasing the prevalence of ACF as well as the risk of CRC (P<0.001).

Conclusions: These results suggested that ACF may serve as a reliable surrogate biomarker for human colorectal carcinogenesis. The use of ACF as an endpoint may enable the size, duration, and cost of CRC chemoprevention studies to be reduced.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A12.
Abstract A18: Detection rates of thyroid, breast, and prostate cancers by medical check-up programs for asymptomatic adults in Korea
Authors: Choi Yoon-Ho , Jeong Ok-Soon
Published: June 2012

Purpose: We investigated retrospectively the detection rates of thyroid and breast cancers in women and prostate cancer in men by medical check-ups for screening purpose in asymptomatic volunteers. The cancer detection rates were compared with natural incidences of each cancer from National Cancer Registry (NCR) in Korea.

Materials and Methods: More than 50,000 apparently healthy adults take comprehensive medical check-ups in a year at Center for Health Promotion, Samsung Medical Center, with their own payments of 1,000 US dollars on average. A total of 283 thyroid cancers were detected among 29,498 thyroid ultrasounds in women for 2 years from 2008 to 2009. A total of 72 breast cancers were detected among 34,741 mammographies or breast ultrasounds in women during the same period. And a total of 77 prostate cancers were detected among 41,898 PSA (prostate-specific antigen) tests in men during the same period. The annual detection rate of each cancer was transformed to a cancer incidence per 100,000 persons through multiplying by 100,000. These cancer incidences from organ-specific and facility dependent tests were compared with crude incidences from 2007 National Cancer Registry according to age groups.

Results: Cancer detection rates of check-up programs for asymptomatic adults were much higher than natural incidences in general population for these three cancers. The average costs for thyroid ultrasound, mammography, breast ultrasound, and PSA in Korea are one third of those in US respectively.

Thyroid cancer by age (F) 20∼29 30∼39 40∼49 50∼59 60∼69 70∼

Incidence by check-up 892.9 807.6 1097.3 893.2 865.8 977.2

Natural incidence by NCR 28.8 80.9 144.3 159 108.7 37

Breast cancer by age (F) 20∼29 30∼39 40∼49 50∼59 60∼69 70∼

Incidence by check-up 0.0 165.1 246.8 188.9 242.3 0.0

Natural incidence by NCR 4.7 40.1 110.7 101.7 73.6 39.3

Prostate cancer by age 20∼29 30∼39 40∼49 50∼59 60∼69 70∼

Incidence by check-up 0.0 0.0 22.4 115.1 437.2 835.4

Natural incidence by NCR 0.0 0.1 1.4 18.3 110.7 262.4

Conclusions: Screening asymptomatic individuals is the effective strategy to detect early-stage disease. Specific imaging methods and blood-based test of reasonable prices showed high yields for prevalent cancers in this study. Well-designed check-up programs with considerations for costs and risks may contribute to national projects to detect cancers early. Further investigations are needed to evaluate issues on long-term mortality and possible disadvantages of screening for thyroid, breast or prostate cancers, especially in older people.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A18.
Abstract A27: Comprehensive analysis of glycans on α1-acid glycoprotein from various cancer patients by MALDI-TOF-MS for assigning a prognostic predictor
Authors: Asao Takayuki , Nishimura Toyo , Hayashi Takashi , Kuwano Hiroyuki , Yazawa Shin
Published: June 2012

α1-Acid glycoprotein (AGP) is well-known as an acute-phase protein, a major plasma glycoprotein with highly glycosylated, branched N-linked glycans and one of the markers for inflammation. In our previous study (Cancer 101:2825–2836, 2004), with the aid of crossed affinoimmunoelectrophoresis (CAIE), glycoforms of plasma AGP from various cancer patients could be easily determined based on the degrees of branching and extent of fucosylation characterized by reactivities with Con A lectin and Aleuria aurantia lectin, respectively. Results clearly indicated that patients with advanced malignancies who had AGP glycoforms that contained highly fucosylated tri- and tetraantennary glycans for long periods after surgery were likely to have a poor prognosis. However, patients who had AGP glycoforms with no such changes were expected to have a good prognosis irrespective of their clinical stages.

In this study, we purified AGP from plasma samples of the same patients and then analysed detailed structures of their glycans involving a new tumor marker using a high throughput glycosylation kit (BlotGlyco, Sumitomo Bakelite, Tokyo, Japan) combined with MALDI-TOF-MS analysis. More than two hundreds of glycan structures were assigned and relative abundance of each glycan was calculated. Follow-up studies of the relative abundance of glycans indicated that the abundance of fucosylated tri- and tetraantennary glycans in patients with a poor prognosis was quite high, and most of which were estimated to form sialyl-LeX structures (NeuAcα2,3Galβ1,4[Fucα1,3]GlcNAcβ) with the non-reducing end sialyl residues. Whereas, in those with a good prognosis, such an abundance was found to be as low as in healthy controls. These results indicated that no distinct difference was observed from our previous CAIE data and that more precise glycan structures instead of glycoforms could be easily assigned by the present method, providing an aberrant marker for predicting the fate of patients after surgery.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A27.
Abstract A35: A role for drug resistance in hepatocellular carcinoma: Upregulatation of CD133, activation of IGF-1R signaling, and IGF-1R nuclear translocation
Authors: Bodzin Adam S. , Wei Zhengyu , Hurtt Reginald S. , Doria Cataldo
Published: June 2012

Introduction: Hepatocellular carcinoma (HCC) is an aggressive neoplasm that is resistant to chemotherapy with mechanisms underlying this drug resistance not well understood. CD133 is a known cancer stem cell (CSC) marker whose high expression is associated with aggressive tumor behavior and poor prognosis. The insulin-like growth factor 1 receptor (IGF-1R) signaling pathway has been shown to play a significant role in tumor behavior. To examine possible mechanisms of drug resistance in HCC, we investigated the role of CD133 expression and IGF-1R signaling activation using geftinib.

Methods: We evaluated and separated five different human HCC cell lines (Mahlavu, Huh7, HepG2, Hep3B, PLC/PRF/5) using based on CD133 expression. We subjected these cells to geftinib at different doses, and determined IGF-1R signaling pathway activation using immunoblotting against relevant proteins in the pathway. CD133 mRNA level was examined using quantitative real-time PCR and its expression level was detected using immunofluorescence imaging and flow cytometry after drug treatment. Cell viability and sensitivity to drug treatment were measured using the MTT assay.

Results: HCC cell lines showed variable percentages of total cell populations expressing CD133: Mahlavu 0.12 %, HepG2 46 %, Huh7 80.2 %, Hep3B 98.2 %, and PLC/PRF/5 83.5 %. Mahlavu and PLC/PRF/5 were found to be the most resistant cell lines even at higher doses (17.5 uM). Since Mahlavu cells displayed reduced CD133 expression, experiments were focused on this cell line to evaluate the CD133 expression changes after geftinib treatment. After three rounds (9 days) of high dose geftinib treatment, CD133 expression was increased in a dose dependent manner; the percentages of total cell populations expressing CD133 increased to 43.9 % at 10 uM concentration and 52.9 % at 15 uM concentration as compared to 0.12 % in untreated cells. In addition, we found a significant increase in IGF-1R and AKT phosphorylation as well as IGFBP3 expression in those geftinib treated cells. Furthermore, after cell sorting of Huh7 cells by CD133 expression using flow cytometry, we observed that CD133 positive cells showed more resistant to geftinib treatment. Immunofluorescence imaging analysis demonstrated that increased IGF-1R protein translocated to nuclei after geftinib treatment.

Conclusion: Geftinib treatment enhanced CD133 expression level and activated IGF-1R signaling in HCC Mahlavu cells, one of the possible mechanism could be the nuclear translocation of IGF-1R. Our findings underscore the importance of a combined therapeutic approach with geftinib and IGF-1R blockage in the treatment of human HCC.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A35.
Abstract A46: Glycolysis and oxidative phosphorylation in cervical cancer: Correlation with FDG PET/CT and its prognostic implication
Authors: Chung Hyun Hoon , Kim Kidong , Song Yong-Sang
Published: June 2012

Purpose: The usefulness of 2-[18F]-fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) can help predict the presence and the extent of malignant cells. The aims of current study were to investigate the expression patterns of genes or enzymes in glucose metabolism, and to determine whether the FDG PET/CT finding correlates with these proteomic markers in surgical specimens. Patients and Methods: Fifty patients with uterine cervical cancer who underwent [18F]FDG PET/CT before treatment were included in this study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (GLUT1), glucose transporter 3 (GLUT3), hypoxia-inducible factor-1α (HIF-1α), hexokinase 2 (HK2), glycolysis markers (pyruvate kinase M2 (PKM2), phosphofructokinase (PFK), glycoaldehyde-phosphate dehydrogenase (GAPDH), pyruvate dehydrogenase (PDH)), electron transporter chain marker (β-F1-ATPase), mitochondrial transcription factor A (TFAM), oncogene (c-Myc), and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α).

Results: In vivo glucose uptake of primary cervical cancer (R = −0.298, P = 0.036) and metastatic lymph nodes (R = −0.298, P = 0.037), as assessed by FDG uptake inversely correlates with the mitochondrial biogenesis determined by immunohistochemical staining of PGC-1α. Cellular GLUT1 expression was also inversely correlated with the expression of PGC-1α (R = −0.413, P = 0.003). Moreover, the level of mitochondrial oxidative phosphorylation expressed by β–F1-ATPase inversely correlates with that of PFK (r = −0.337, P = 0.021). Expression of PGC-1α was lower in squamous cell carcinoma than that of adenocarcinoma (P < 0.001), however, GLUT1 expression was higher in squamous cell carcinoma (P = 0.003). Of interest, HK2 expression in primary tumor was significantly lower in patients with lymph node metastasis (P = 0.003).

Conclusion: The results highlight the relevance of the alteration of the glucose metabolism by aerobic glycolysis in cervical cancer, and affording a mechanistic explanation for FDG PET/CT imaging.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A46.
Abstract A64: Effects of genetic polymorphisms of innate immunity genes on the noncardia gastric cancer risk
Authors: Kim Jeongseon , Cho Young Ae , Choi Il-Ju , Cho Soo-Jeong , Kim Chan Gyoo , Lee Jong Yeul , Kim Young-Woo
Published: June 2012

Background and Objective: Increasing evidence suggests that polymorphisms in innate immunity genes are associated with Helicobacter pylori (H. pylori)-induced inflammation and may influence susceptibility to developing noncardia gastric cancer. Therefore, we investigated the effect of polymorphisms of TLR2, TLR4, and CD14, their combination and interaction with environmental factors on the noncardia gastric cancer risk in a Korean population.

Methods: We genotyped four polymorphisms in three genes (TLR2, rs1898830 A>G; TLR4, rs10759932 T>C, rs10983755 A>G; CD14, rs2569190 T>C) in a case-control study of 487 noncardia gastric cancer patients and 487 sex- and age-matched healthy controls. Multiple logistic regression models were used to detect the effects of genetic polymorphisms and environmental factors, which was stratified by the histological type of gastric cancer.

Results: TLR4 rs10983755 variant allele carriers were found to have a higher risk of intestinal type gastric cancer than homozygous wild-type carriers (OR [95% CI] = 1.40 [1.01–1.96], P = 0.046). Other genetic variants did not show any association with noncardia gastric cancer risk. When we examined the combined effect with other polymorphisms, the increased risk of intestinal type gastric cancer among TLR4 rs10983755 variant allele carriers compared to wild-type homozygous carriers were observed only among homozygous wild-type carriers of TLR2 rs1898830 (OR [95% CI] = 1.97 [1.24–3.12], P = 0.004) or CD14 rs2569190 (OR [95% CI] = 1.95 [1.31–2.91], P = 0.001). In addition, the effect of TLR4 rs10983755 variant allele on intestinal type gastric cancer was stronger among H. pylori-positive participants who are under 55 years old, smoke tobacco and drink alcoholic beverages.

Conclusion: These results suggest that the genetic polymorphisms of these innate immunity genes are associated with the development of H. pylori-associated noncardia gastric cancer.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A64.
Abstract B15: Distribution of HPV genotypes in cervical intraepithelial lesions and cervical cancer in Tanzanian women
Authors: Vidal Adriana , Murphy Susan K. , Hernandez Brenda , Oneko Olola , Overcash Francine , Hoyo Cathrine
Published: June 2012

Context: Cervical cancer incidence is four times higher in eastern and southern Africa than in North America and Europe. Infection with human papillomavirus (HPV) is associated with low-grade (LGSIL) and high-grade (HGSIL) intraepithelial lesions of the uterine cervix, and high-risk (HR) HPV DNA is detected in almost all invasive cervical cancers (ICC). Although vaccine development will rely on knowledge of HPV genotypes characteristic in HSIL, LSIL and cancer in different populations, these genotypes remain uncharacterized in African populations.

Objective: To describe HPV genotype distribution in women living in Northeastern Tanzania.

Methods: 215 study participants were recruited from the Reproductive Health Clinic at Kilimanjaro Christian Medical Center (KCMC). Cervical scrapes were used to grade cervical intraepithelial neoplasia (CIN). These specimens were used to detect HPV infection for 60 genotypes. Proportions were determined and ranked.

Results: Of 215 women identified from the KCMC, 79 (36.7%) were HPV-positive (20 had no evidence of cytological abnormality, 12 had CIN1, 14 had CIN2–3, and 33 had cervical cancer). Overall, 31 HPV genotypes were detected, and multiple HPV infections were more common than single infections in CIN and ICC. The prevalence of HPV infection increased with lesion grade (14% in controls, 66% in CIN1 cases, 87% in CIN2/3 and 89% in ICC). Whereas in ICC, the three most common genotypes were HPV16, 35/45/6, and 18/73, the most common genotypes in CIN2–3 were HPV53, 58 and 84/83, and in CIN1 they were HPV35, 45, 53/58/59. Among controls, the most prevalent genotype was HPV58 with HPV 16, 35, 52, 66 and 73 occurring equally. Restricting analyses to HIV-negative women revealed that HR-HPV genotypes are most frequent in ICC.

Conclusions: While small sample size limits interpretation, these findings suggest HPV genotypes other than 16 and 18 may drive cervical cancer risk in this region. The low frequency or absence of HPV 16 and 18 in CIN1 or CIN2–3 has implications for current cytology and HPV-based screening as well as for vaccine development for this region. Larger studies are required.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):B15.
Abstract B2: Effects of individual and combined diet and exercise intervention in postmenopausal women on adiponectin and leptin
Authors: Abbenhardt Clare , Potter John D. , Mason Caitlin E. , Xiao Liren , Blackburn George L. , Bain Carolyn , Ulrich Cornelia M. , McTiernan Anne , Campbell Kristin L. , Alfano Catherine M. , Wener Mark H. , Duggan Catherine , Foster-Schubert Karen E. , Kong Angela
Published: June 2012

Introduction: Obesity and sedentary lifestyles are modifiable risk factors for several chronic diseases. Adiponectin and leptin play central roles in energy balance, insulin homeostasis and lipid/glucose metabolism. We examined the individual and combined effects of dietary weight loss and/or exercise on serum adiponectin and leptin concentrations.

Methods: We conducted a 12-month randomized controlled trial in 439 overweight/obese postmenopausal women to examine biomarkers of breast cancer risk. Participants were randomly assigned to dietary weight loss (D) (N=118), moderate-to-vigorous intensity aerobic exercise (E), 225 minutes/week (N=117), combined diet + exercise (D+E) (N=117), or control (N=87). Blood samples were taken at baseline and 12 months follow-up. Changes in adiponectin and leptin were measured via radioimmunoassay.

Results: Adiponectin increased significantly over the intervention period in the D+E (+6.6%; p=.0001) and D group (+9.5%; p<.0001), compared to controls (−0.4%). No statistically significant adiponectin changes were observed in the E intervention. In all intervention groups leptin decreased significantly compared to controls (D+E −40.1% p<.0001; D −27.1% p<.0001; E −12.1% p=0.005). When stratified by baseline BMI, we observed slightly stronger increases in adiponectin among those with BMI ≥ 30kg/m2 in the D+E intervention. Changes in leptin with the intervention were equally strong independent of baseline BMI. With increasing weight loss, adiponectin increased independent of the intervention group (D, D+E or E).

Conclusion: Our study showed that a dietary weight-loss intervention had strong effects on adiponectin levels, independent of exercise. We also observed that lifestyle interventions associated with weight loss, are successful in reducing serum leptin concentrations.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):B2.
Abstract B32: Interactive, automated phone outreach encourages health plan members to have recommended mammograms and leads to early breast cancer detection
Authors: Freeman Lisa , Powers Janet
Published: June 2012

Background: Interactive, automated phone calls let health plans have timely, relevant conversations with their members about key health topics. This channel is effective in widely reaching individuals of all ages and socio-demographic categories and can offer several language alternatives. In one program multiple goals can be achieved –sharing health information, determining planned behavior, assessing and addressing barriers, and increasing engagement.

Objective/purpose: As a way to increase key quality ratings, health plans reach out to eligible members to encourage them to have their age-appropriate screenings. This communication is designed to provide health plans with a better understanding of screening barriers and how to address these issues. A parallel goal is earlier detection of breast cancer diagnoses among members. Designed as an engaging conversation, this outreach also increases members' satisfaction and loyalty to their health plan.

Methods: This program used proprietary interactive voice recognition technology and communication expertise to develop an interaction aimed at reminding members of the importance of having their mammogram.

Results: The outreach determined that 85% (3,068) of all members contacted planned to schedule their mammogram. After conducting outcomes analysis, based on claims data, 19% (597) of the members who said that they planned to have their mammogram screened positive for breast cancer and received treatment.

Discussion/Conclusions: The ultimate goal of this outreach is to engage women in their health and increase the number who speak with their doctor and have a mammogram. While additional analysis is still being conducted, it can be determined that interactive, automated outreach is an effective method to breast cancer early detection and prevention.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):B32.
Abstract B41: A mouse model for inflammation-driven lung tumorigenesis
Authors: Melkamu Tamene , Qian Xuemin , O'Sullivan Gerry , Kassie Fekadu
Published: June 2012

The link between chronic inflammation and cancer development has lately gained extensive epidemiological and experimental support, particularly in organs like liver, stomach, colon, and lung. Although experimental models are available to study inflammation-driven tumorigenesis in the liver, stomach, and colon, no such models are available for lung cancer. Therefore, the objective of the present study is to develop a model for inflammation-driven lung tumorigenesis. A/J mice received four intraperitoneal injections (two doses/week) of the tobacco smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) at a dose level of 50 mg/kg body weight. Beginning one week after the last dose of NNK, the mice were given weekly intranasal instillations of lipopolysaccharide (LPS, 10ug/mouse), a potent inflammation-inducing agent, until the end of the study at week 27. Upon termination of the study, tumors on the surface of the lung were counted, their size determined and histopathologically analyzed. Moreover, we analyzed alterations in the expression of inflammation- and tumorigenesis-related proteins and microRNAs (miRs) by Western immunoblotting and qRT-PCR, respectively. Chronic exposure NNK-treated mice to LPS increased the number and size of lung tumors (47.3 ± 11 tumors/mouse for the NNK plus LPS group versus 28 ± 8 tumors/mouse in the NNK only group).

Furthermore, lung tumors in the NNK plus LPS treated mice were significantly larger than the lung tumors of the mice challenged with NNK alone.

Multiplicities of lung tumors in LPS-treated mice were similar to those mice given the vehicle. Multiplicities of the histopathological lesions pulmonary hyperplastic foci, adenoma, adenoma with dysplasia and adenocarcinoma in the NNK only group were 3.0 ± 1.2, 7.1 ± 2.9, 1.3 ± 1.1, and 0.3 ± 0.5/mouse, respectively. The corresponding frequencies of the lesions in the NNK plus LPS group were 3.1 ± 1.8, 11.8 ± 5.2, 3.9 ± 1.8, and 0.6 ± 0.7/mouse. Western immunoblotting studies showed that LPS exposure of NNK-treated mice enhanced activation of NF-kappaB, STAT3, and Akt but caused down-regulation of the tumor suppressor protein PTEN. Further, analyses of levels of five carcinogenesis-related microRNAs (miR-21, miR-146a, miR-150, miR-155 and miR-21, and miR-181b-1) showed increases in the expressions of miR-155 and miR-21. Levels of miR-155 and miR-21 were increased by 2.3-fold and 1.9-fold, respectively, in mice treated with NNK plus LPS group as compared to mice treated with NNK. Moreover, levels of miR-155 and miR-21 were increased by 10.5-fold and 4.7-fold, respectively, in LPS treated mice compared to vehicle-treated mice. In summary, our results demonstrate that LPS-induced chronic lung inflammation enhances lung tumorigenesis. This model could be a vey useful tool to understand the role inflammation in lung tumorigenesis and for identification of anti-inflammatory and lung cancer chemopreventive agents.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):B41.
Abstract B42: Lack of chemopreventive effects of metformin in azoxymethane-induced rat colon carcinogenesis
Authors: Rao Chinthalapally V. , Janakiram Naveena B. , Mohammed Altaf , Madka Venkateshwar , Qian Li , Brewer Misty , Duff Ashley , Zhang Yuting , Steele Vernon E.
Published: June 2012

Metformin, an insulin-lowering agent, has been associated with decreased cancer risk in epidemiologic studies in diabetic patients. Short-term preclinical and clinical observations also supported inhibition of colonic precancerous lesions. However, recent meta-analysis studies show that metformin or related drugs may reduce risk of pancreatic and hepatocellular carcinoma but a non-significant inverse correlation with colon cancer risk. The present study explores a systematic analysis of chemopreventive efficacies of metformin on a well established model of colon carcinogenesis, using colonic preneoplastic lesions and adenocarcinomas as end points. Effect of dietary metformin (100 ppm, 400 ppm, 800 ppm to 1,600 ppm) on AOM-induced aberrant crypt foci (ACF) development; and a dietary metformin (500 ppm and 1,000 ppm) on AOM-induced colon adenocarcinoma was studied in F344 rats. ACF and tumor efficacy endpoints were carried out on AOM-treated 8-week-old rats (48 per group) fed the control AIN-76A diet. Either three days (ACF Study) or 4 weeks (adenocarcinoma study) after carcinogen treatment, rats were fed the diets containing different doses of metformin. ACF and colon adenocarcinomas were determined at 8 and 48 weeks after AOM-treatment, respectively. Dietary metformin at 100 and 400 ppm had no significant effect on the colonic ACF formation; whereas at higher doses a significant increase was observed in the total ACF (37%) and multicrypt ACF by 43%. In long term bioassay, dietary metformin at 500 and 1,000 ppm had no significant effect on adenocarcinoma incidence. With regard to colon adenocarcinoma multiplicity, metformin at both dose levels failed to provide any inhibitory effect, albeit, modest increase (∼20%) in adenocarcinoma multiplicity at high dose level was seen. Similarly, dietary metformin fail to show any inhibitory effect on colon tumor volume. Rats that were fed with metformin fail to show significant effects on markers of cell proliferation and apoptosis in colonic tumors. These observations show, for the first time, that metformin tested at different dose levels does not provide chemopreventive effects at the preneoplastic lesion stage or at adenocarcinoma stages in a well-established rat colon cancer model. Further studies are warranted to understand the discrepancies between preclinical models and more so in human clinical observations on the potential beneficial effects of metformin for colon cancer risk.

{This work is supported by NCI-N01 CN-53300}

Citation Information: Cancer Prev Res 2011;4(10 Suppl):B42.
Abstract B51: Genetic variation in nucleotide excision repair pathway genes, pesticide exposure, and prostate cancer risk
Authors: Barry Kathryn Hughes , Zheng Tongzhang , Alavanja Michael CR , Berndt Sonja I. , Koutros Stella , Andreotti Gabriella , Sandler Dale P. , Burdette Laurie A. , Yeager Meredith , Freeman Laura E. Beane , Lubin Jay H. , Ma Xiaomei
Published: June 2012

Introduction: Previous research has demonstrated increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, human biomonitoring studies indicate increased genetic damage with pesticide exposure. Given that the nucleotide excision repair (NER) pathway repairs a broad range of DNA damage, we evaluated interactions between pesticide use and 324 single nucleotide polymorphisms (SNPs) tagging 27 NER genes among 776 prostate cancer cases and 1,444 male controls in a nested case-control study of white pesticide applicators in the Agricultural Health Study, a prospective cohort of pesticide applicators in Iowa and North Carolina.

Methods: We used likelihood ratio tests from logistic regression models to determine P-values for interactions between three-level pesticide variables (none/low/high) based on lifetime days of use weighted to an intensity score and SNPs (assuming a dominant model). We employed the False Discovery Rate (FDR) method to adjust for multiple comparisons.

Results: Of the seventeen interactions that met FDR<0.2, three also displayed a monotonic increase in prostate cancer risk with increasing pesticide use in one genotype group and no significant association in the other group. Men carrying the variant A allele at ERCC1 rs2298881 exhibited increased prostate cancer risk with high versus no fonofos use (Odds Ratio (OR): 2.98; 95% Confidence Interval (CI): 1.65–5.39; Pinteract=3.6×10–4; FDR-adjusted P=0.11). Men carrying the homozygous wild-type TT genotype at two correlated CDK7 SNPs, rs11744596 and rs2932778 (r2=1.0), exhibited increased prostate cancer risk with high versus no carbofuran use (OR: 2.01; 95% CI: 1.31–3.10 for rs11744596; Pinteract=7.2×10–4; FDR-adjusted P=0.09). In contrast, we did not observe associations with prostate cancer among men with other genotypes at these loci.

Conclusions: While requiring replication, our findings suggest a role for NER genetic variation in pesticide-associated prostate cancer risk.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):B51.
Abstract B54: Reproductive status at first diagnosis influences risk of radiation-induced second primary contralateral breast cancer in The WECARE Study
Authors: Brooks Jennifer D. , Thomas Duncan C. , Haile Robert W. , Smith Susan A. , Capanu Marinela , Bernstein Jonine L. , Shore Roy E. , Boice John D. , Stovall Marilyn , Reiner Anne S. , Bernstein Leslie , John Esther M. , Lynch Charles F. , Mellemkjaer Lene , Knight Julia A.
Published: June 2012

The breast undergoes changes in composition, function and hormonal milieu during puberty, pregnancy, lactation and postmenopausal involution. These changes may influence the susceptibility of the breast to carcinogens, including exposure to ionizing radiation.

The Women's Environmental, Cancer and Radiation Epidemiology (WECARE) Study is a multi-center, population-based, case-control study of 708 women (cases) with asynchronous contralateral breast cancer (CBC) and 1,399 women (controls) with unilateral breast cancer (UBC). Radiation therapy (RT) records were used to reconstruct the radiation dose to the location in the contralateral breast where the second cancer arose (or to the equivalent breast location for UBC controls). Rate ratios (RR) and 95% confidence intervals (CI) were computed to assess the relationship between reproductive status at first breast cancer diagnosis, RT and risk of CBC, adjusting for known breast cancer risk factors: age at (first) diagnosis, menopausal status/age at menopause at first diagnosis, age at menarche, number of full-term pregnancies, first degree family history of breast cancer, histology and stage of first primary breast cancer, and treatment (chemotherapy/hormonal therapy).

Women who were nulliparous at first diagnosis and exposed to ≥1 gray (Gy) to the contralateral breast, had a higher risk of CBC than unexposed nulliparous women (RR=2.2, 95% CI 1.2–4.0). An increased risk was not seen in RT exposed parous women (RR=1.1, 95% CI 0.8–1.4). Women treated with RT who later became pregnant had a greater risk of CBC compared with unexposed women who also became pregnant (RR=6.0, 95% CI 1.3, 28.4), though these results were based on small numbers. The effect of radiation on risk of CBC did not vary by number of pregnancies, history of breast feeding or menopausal status at the time of first breast cancer diagnosis.

These results suggest that RT may be associated with an increased risk of developing a second breast cancer in nulliparous but not parous women.

Women who become pregnant after first breast cancer diagnosis may also be at an increased risk of CBC. It is possible that RT could be the initiating event, leading to preneoplastic cellular changes that are then promoted by the hormonal changes of a subsequent pregnancy.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):B54.
Abstract B62: Differential influence of vitamin D on the tumor promoting eicosanoid PGE 2
Authors: Qin Wenyi , Dahlman Julie , Rebecca Lessard , Sauter Edward
Published: June 2012

Numerous lines of evidence point to the tumor promoting properties of prostaglandin (PG)E2. Preclinical studies have demonstrated the ability of both vitamin D (vitD) and celecoxib to downregulate the ecisanoid. We hypothesized that the two agents would work synergistically. The purpose of the study was to determine the dose dependent effects of vitD, with or without celecoxib. 24 women were prospectively enrolled and randomized in double blind fashion for one month (postmenopausal) or one menstrual cycle (premenopausal) to one of four daily treatment regimens: placebo, 400 IU vitD, 2000 IU vitD, or 2000 IU vitD + 400 mg celecoxib. Breast nipple aspirate fluid (NAF) and serum were collected. Both breast specific and systemic levels of PGE2 were measured. There was a significant dose dependent increase in 25(OH)D levels (p<.01). The post-treatment levels of NAF (but not serum) PGE2 were lower and the decrease greater in the 2000 IU vitD than in the other groups (p<.05) of normal risk women. A similar effect was not observed in women at increased breast cancer risk, nor in women receiving vitD + celecoxib. These findings suggest the potential of vitamin D, given in adequate dose, at lowering a key cancer promoting enzyme in women of normal breast cancer risk.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):B62.