bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1777: The skin cancer chemotherapeutic agent PEP005 is a substrate for the epidermal multidrug transporter (ABCB1) and targets tumor vasculature
Authors: Li Luowei , Shukla Suneet , Lee Andrew , Ambudkar Suresh , Yuspa Stuart H.
Published: February 2011

Ingenol-3-angelate (PEP005), extracted from Euphorbia peplus, is currently in clinical trials for eradicating basal cell carcinoma (BCC), actinic keratosis and squamous cell carcinoma (SCC) in situ by topical application. Although structurally related to phorbol esters and a PKC activator, topical PEP005, but not phorbol 12-myristate 13-acetate (PMA), inhibited the growth of subcutaneous tumors derived from PAM212 (mouse SCC) and B16 (mouse melanoma). PEP005 and PMA both induced acute neutrophilic inflammation on mouse skin, but only PEP005 caused subcutaneous hemorrhage and vascular damage. Both PEP005 and PMA activated Erk1/2 in epidermis, but PEP005 also activated Erk1/2 in skin dermal fibroblasts and endothelial cells. Pretreatment with topical cyclosporin A (CsA), verapamil or XR9576, modulators of P-glycoprotein (P-gp), prevented PEP005-induced hemorrhage but not neutrophil infiltration. CsA also impaired Ing3A's anti-cancer activity while the anti-inflammatory dexamethasone did not. PEP005, but not PMA, blocked photoaffinity labeling of human P-gp with [125I]-Iodoaryazidoprazosin and inhibited P-gp mediated drug resistance to HCT-15 cells. The intracellular levels of PEP005 were significantly lower in P-gp expressing cells and treatment with XR9576 increased the levels to those of cells that do not express P-gp, demonstrating that PEP005 binds to and is transported by P-gp. Taken together, our results suggest that P-gp mediated absorptive transport, dermal penetration and vascular damage contribute to the anti-cancer activity of PEP005 in vivo.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1777.
Abstract 1778: Nimotuzumab, a humanized antiepidermal growth factor receptor antibody, interacts with EGFRvIII
Authors: Jaramillo Maria L. , Grothe Suzanne , Baardsnes Jason , Banville Myriam , Paul-Roc Beatrice , Tikhomirov Ilia A. , Thompson Sean EL , O'Connor Maureen
Published: February 2011

Introduction: Glioblastomas frequently overexpress a variant form of EGFR, called variant III (EGFRvIII), which has an in-frame deletion of an 801-bp sequence in the extracellular domain. EGFRvIII does not bind EGF ligand but exhibits constitutive kinase activity that results in enhanced transformation, reduced apoptosis, and resistance to therapy. Nimotuzumab (Nmab) is an EGFR-targeting antibody that has demonstrated encouraging results in early clinical trials treating adult and pediatric brain tumors. Here we present data characterizing the interaction of Nmab with EGFRvIII.

Methods: Binding of Nmab to the extracellular domain of wtEGFR and EGFRvIII was first characterized by SPR biosensor analysis: Nmab was captured via its Fc domain and varying concentrations of EGFRvIII and EGFRwt were flowed. Flow cytometry analysis was subsequently performed using a parental U87MG glioblastoma cell line and derivatives which were engineered to overexpress either wtEGFR or EGFRvIII.

Results: Nmab bound EGFRvIII and EGFRwt with similar affinity, which was in the 10−8 M range. This KD is consistent with the previously reported affinity constant of Nmab for EGFRwt (Telavera et al, 2009). Binding was further analyzed by flow cytometry. Nmab bound both EGFRwt and EGFRvIII expressed on the surface of parental U87MG, U87MG EGFRvIII and U87MG wtEGFR cells. Additional data concerning effects of Nmab on EGFRvIII expressing cell lines will be presented.

Conclusion: Nmab binds to wtEGFR and EGFRvIII with similar affinity, which supports development of the antibody as a therapeutic for glioblastoma. In U87MG glioblastoma cells, synergistic activity of Nmab in combination with radiotherapy has been previously reported (Diaz Miqueli et al, 2009). Nmab is currently being tested in an advanced randomized study in the first line setting for the treatment of adult glioma. Nmab is being tested in combination with radiation plus temozolomide, vs radiation plus temozolomide alone, with preliminary results expected in the second half of 2010.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1778.
Abstract 1779: Serum level of DKK1 as a marker for predicting tumor recurrence of hepatocellular carcinoma
Authors: Tung Edmund KK , Mak Carmen KM , Lee Joyce MF , Li Jin J. , poon Ronnie TP , Lai Ching L. , Luk John MC , Ng Irene O. L
Published: February 2011

Dickkopf-1 (DKK1), an inhibitor of Wnt/beta-catenin signaling pathway, is upregulated in various cancers including HCC. However, the clinical significance of serum DKK1 in hepatocellullar carcinoma (HCC) remains to be determined. The objective of this study was to investigate the clinical significance of DKK1 and its prognostic value in predicting survival and tumor recurrence in human HCC. Two independent cohorts with 217 and 100 pairs of tumors and corresponding nontumor livers were employed for microarray analysis and real time-quantitative PCR (qPCR), respectively, to investigate the DKK1 transcript levels in human HCC samples. The serum levels of DKK1 were determined in 50 patients with early HCC, 50 patients with advanced HCC, 50 patients with cirrhosis, 50 hepatitis B virus (HBV) carriers, and 30 HCC patients after liver resection, using sandwich ELISA system. Transcript level of DKK1 in the human HCCs was found to be significantly upregulated as compared with the corresponding nontumorous livers in both microarray (P < 0.001) and qPCR cohorts (P < 0.001). Increased expression of DKK1 was associated with advanced tumor stage (P < 0.001), venous infiltration (P < 0.001), high serum alpha-fetoprotein (AFP) level (P < 0.001). Higher level of DKK1 correlated with both poorer overall survival (P = 0.016) and tumor recurrence (P = 0.014). On the other hand, the serum DKK1 level in the group of HBV carriers without HCC (as control) was not significantly different from that of the cirrhosis group (P = 0.086). In contrast, the serum DKK1 level was significantly higher in patients with early HCC (P < 0.001) and advanced HCC (P < 0.001), as compared with the HBV carrier group. Furthermore, the serum DKK1 level in patients after liver resection was significantly reduced (P < 0.001). Higher serum DKK1 level was associated with tumor recurrence (P = 0.046). To conclude, our data have demonstrated that tissue and serum DKK1 levels were significantly and progressively elevated during HCC formation and progression. DKK1 has prognostic role in predicting overall survival and disease-free survival of HCC patients, and serum DKK1 is a potential biomarker for predicting tumor recurrence.

(The study was supported in part by a grant from the NSFC/RGC Joint Research Scheme [N_HKU 716/06] and an RGC Collaborative Research Grant [HKU 1/06C]. IOLN is a Loke Yew Professor in Pathology)

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1779.
Abstract 1787: Dual targeting of PI3K and mTOR results in synergistic growth inhibition in NSCLC cells
Authors: Chao Herta H. , Zito Christopher , Jilaveanu Lucia , Anagnostou Valsamo , Rimm David , Bepler Gerold , Camp Robert , Kluger Harriet M.
Published: February 2011

Background:

Alterations of components in the PI3K/mTOR pathway can result in malignant transformation and are found in a multitude of human cancers including non-small cell lung cancer (NSCLC). Our purpose was to characterize expression of p85 and p110α PI3K subunits in NSCLC specimens and assess the association with mTOR expression, and to study the effects of co-inhibiting PI3K and mTOR in NSCLC cell lines.

Methods:

Using Automated Quantitative Analysis (AQUA), a novel method of in situ protein measurement, we quantified expression of PI3K subunits in two cohorts of 251 and 192 resected NSCLC specimens. AQUA scores were correlated with clinical and pathological variables and previously published AQUA scores for mTOR. We studied changes in viability of 6 NSCLC cell lines exposed to two PI3K inhibitors, LY294002 and NVP-BKM-120, alone and in combination with rapamycin, and assessed the activity of a dual PI3K/mTOR inhibitor, NVP-BEZ-235, which is in clinical development.

Results:

p85 and p110α tend to be co-expressed (p<0.001), and higher expression of p85 was seen in adenocarcinomas than squamous cell carcinomas (SCC). High expression of p85 correlated with poor survival (p< 0.0075). Expression of p110α correlated with mTOR (ρ=0.30). In 6 NSCLC cell lines (3 adenocarcinomas, 3 SCC) the addition of rapamycin to LY294002 or NVP-BKM-120 was highly synergistic. Of note, even small concentrations of rapamycin (1ηM) resulted in sensitization to the PI3K inhibitors, and similar reduction in viability was seen with the addition of 1ηM, 100ηM and 1000ηM of rapamycin. NVP-BEZ-235 was highly active in NSCLC cell lines with IC50s in the ηM range and resultant down-regulation of pAkt and pP70S6K.

Conclusions:

PI3K is associated with decreased survival in NSCLC, suggesting that it is a good drug target for this disease. Concurrent inhibition of PI3K and mTOR is synergistic in NSCLC cell lines. Dual inhibition of PI3K and mTOR by NVP-BEZ-235 is promising and should be further evaluated in clinical trials for patients with NSCLC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1787.
Abstract 1792: Association of enhanced IGF-1R signaling and HBV/inflammation with poor HCC prognosis
Authors: Chang Te-Sheng , Lee Kam-Fai , Tung Shui-Yi , Kuo Liang Mou , Huang Yen-Hua
Published: February 2011

Hepatocellular cell carcinoma (HCC) associated with chronic HBV hepatitis tends to have a more unfavorable prognosis. Recently, a global transcriptome analysis by Boyault's group suggested that HBV infection would result in chromosome instability and activation of insulin-like growth factor receptor (IGFR)/AKT signaling pathway (but not the β-catenin pathway) of a subgroup of HCC. As both chronic inflammation and viral infection have been demonstrated to be important promoters for HCC tumorigenesis, we investigated the potential effects of HBV and chronic inflammation on the activation of IGF signaling pathway. By using the paired HBV- positive and HBV-negative HCC cell lines (HepG2.2.15 (HBV+) vs. HepG2 (HBV-); and Hep3B (HBV+) vs. Huh7 (HBV-)), we found the increased expression of IGF1 receptor at both gene (by RT PCR) and protein levels (by Western blotting) in HBV-positive HCC cell lines. Meanwhile, the IGF-1R activation signaling (such as phospho-IGF-1R and phospho-Akt) was also significantly increased in HBV-positive HCC cell line (Hep3B vs. Huh7). To further examine the role of inflammatory cytokine(s) in IGF-1 signaling of HCC cells, increasing dilution folds of LPS (lipopolysaccharide)- stimulated monocyte-differentiated U937 cell condition medium (U937-CM) were added in culture medium for treatment of HepG2 and HepG2.2.15 cells. By Western blotting analysis, the chronic inflammation condition showed enhancement of the IGF-1R protein expression in the HepG2.2.15 while comparing with the HepG2 cells. These observations suggested that the inflammatory stress may further elevate the IGF-1R expression in HBV-positive HepG.2.2.15 cell line. The associated clinical implication was further evaluated by high throughput tissue microarray. Our results revealed a negative correlation between phospho-IGF-1R expression and disease-free survival. In summary, our work showed that both HBV and chronic inflammation promoted IGF-1R activation signaling which may result in the poor prognosis of a subgroup of HCCs. The underlying mechanism(s) contributing the IGF-1R-mediated signal to the ominous disease outcome still needs further investigation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1792.
Abstract 1806: Efficacy of MM121 in ER+ and triple negative breast cancer studies
Authors: Nie Lin , Burenkova Olga , Adams Sharlene , Kalra Ashish , Fulgham Aaron , Xiao Dongmei , Grantcharova Viara , Onsum Matt , Wille Lucia , Moulis Sharon , Garcia Gabriela , Moyo Victor , Kubasek Bill , Nielsen Ulrik
Published: February 2011

In women, breast cancer is among the most common cancers and the fifth most common cause of cancer deaths. Due to the heterogeneity of the disease, 10-year progression free survival can vary widely with stage and type from 98% to 10%. We present data showing that MM-121, a fully human monoclonal anti-ErbB3 antibody, is efficacious in studies of both hormone dependent (ER+) and triple negative (ER-,PR-, Low Erb2) breast cancer lines that express the molecular profile consistent with MM-121 response (co-expression of ErbB3 and HRG).

Using a combination of computational and experimental approaches, ErbB3 was identified as a critical transducer of oncogenic signaling leading to the development of MM-121, a first in class anti-ErbB3 antibody. We have previously demonstrated that MM-121, when used as a single agent, inhibits heregulin-induced signaling events in human cancer cell lines. Moreover, MM-121 caused dose-dependent inhibition of tumor growth in multiple xenograft models of human cancer, including ovarian, renal cell, pancreatic, lung, and prostate cancer.

Estrogen dependent, or ER+ breast cancers, make up about 80% of breast cancers. A standard treatment for ER+ breast cancer includes hormone therapy; however a substantial number of ER+ breast cancers eventually develop resistance requiring additional treatments. Here we show that in ER+ breast cancer cells, MM-121 can block HRG induced ErbB3 activation and VEGF secretion as well as HGF induced pErbB3 in vitro. Additionally, in ER+ breast cancer xenograft models, MM121 is effective in combination with both chemotherapy agents and targeted therapies and may be effective in ER+ breast cancers that are refractory to hormone treatment.

The triple negative breast cancers are characterized by poor prognosis, aggressiveness, and reduced responsiveness to standard treatments. MM-121 used as a single agent therapy was able to suppress tumor growth in triple negative primary human tumors, when grown as xenografts suggesting that MM-121 monotherapy may be clinically efficacious in triple negative breast cancers.

Together, these data suggest that MM-121, when used as a single agent or in combination with other therapies, could offer significant clinical benefit to both ER+ and triple negative breast cancer patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1806.
Abstract 1810: PTEN association with mTOR pathway activation and outcomes in bladder cancer
Authors: Orloff Mohammed , Elson Paul , Yang Yi-Ran , Eng Charis , Hansel Donna E.
Published: February 2011

Background: We have recently identified increased mTOR pathway activation in urothelial carcinoma of the bladder (UCC). We next sought to determine the relationship of PTEN, an upstream negative mediator of the mTOR pathway, to mTOR activity and outcomes in UCC patients.

Methods: Patients with UCC (n=118) were examined for PTEN expression, including intensity of expression (0 no expression, 1+ low, 2+ moderate, 3+ intense expression) and predominant subcellular localization (nuclear, non-nuclear). Results were correlated with the presence of lymph node (LN) metastases, recurrence-free survival (RFS) and overall survival by univariate and multivariate analysis. PTEN intron/exon mutational analysis was performed by denaturing gradient gel electrophoresis (DGGE) and mutational status was correlated with PTEN protein expression in a subset of 91 specimens.

Results: The majority of patients (91/118; 81%) demonstrated moderate to intense expression of PTEN, with PTEN loss in only 2 patients. PTEN was primarily localized to the nucleus in 30/116 (26%) patients, with some level of nuclear PTEN staining in 74/116 (64%) of patients. In LN metastases, reduced PTEN intensity was associated with an increased percentage of phospho-mTOR cells (p=0.02). PTEN mutational analysis identified 3 variants (c.132C>T, c.511C>G, c.892C>G) which were associated with absent PTEN protein expression and diffuse phospho-mTOR expression. Reduced RFS was correlated with positive surgical margins (p=0.09), carcinoma in situ (p=0.09) and nuclear PTEN (p=0.08). Reduced overall survival was significantly associated with metastases (p=0.04) and nuclear PTEN expression (p=0.04). Stepwise multivariable analysis showed an association between reduced RFS and LN metastases (p=0.03), carcinoma in situ (0.05) and nuclear PTEN (p=0.07).

Conclusions: Alterations in PTEN expression and subcellular localization appear to mediate mTOR pathway activity in bladder cancer cells, although few mutations appear to account for reduced PTEN expression. Nuclear localization of PTEN is a relatively new finding and its function in mediating cancer behavior is under investigation. Our finding of worsened outcomes with nuclear PTEN localization warrant further functional investigation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1810.
Abstract 183: Global knock-down of the cancer epigenome
Authors: Hou Pei-Chi Peggy , Yen Ching-Chu , Lee Kuan-Der , Chang Hao-Chun , Cheng Chao-Min , Lin Yi-Shiuan , Sun H. Sunny , Chang Yu-Sun , Huang Tim H.-M. , Hsiao Shu-Huei , Tsai Shaw-Jenq , Leu Yu-Wei
Published: February 2011

Aberrant DNA methylation within the promoter regions is associated with the tumorigenesis, yet no whole epigenomic targeting method has been developed to target all of the aberrant loci. We then aimed to establish a global epigenomic targeting method to efficiently against specific cancer cells. To identify and target all the methylation differences between the estrogen receptor (ER) expressing (MCF7, ER+) versus the nonexpressing (MDA-MB-231, ER−) breast cancer cells, a methylation subtraction method was established. Identified targets was validated by high-throughput sequencing and quantitative PCR, and the efficiency of targeting was validated by the cell death phenotype, increased DNA methylation and reduced expression in the target genes. Targeted methylation within these identified loci specifically killed the MDA-MB-231 cells but not the MCF7 cells either in culture or the tumors grown in immuno-deficient mice. To narrow down the number of targets, we identified and targeted 19 of the estrogen receptor-governed loci that were hypomethylated in the MDA-MB-231, implicating their role in the survival and malignance of these ER− cells. The targeted methylation was sufficient to kill the ER− cells in culture. Among these 19 loci, targeted ENSA methylation alone was sufficient to kill the MDA-MB-231 cell specifically in culture as well as in immuno-deficient mice. Overall, a global targeted methylation methodology was established that could be used to identify and target the methylation differences between two cells. These results indicated that the developed global knock-down method might serve as a whole genome validation and therapeutic alternatives. (Supported in part by NSC 97-2320-B-194-003-MY3, NSC 98-3112-B-194-001 and NSC 97-2627-B-006-003)

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 183.
Abstract 1844: No evidence for genetic factor increasing renal cell cancer risk in Hereditary Leiomyomatosis and Renal Cell Cancer syndrome
Authors: Koski Taru A. , Vahteristo Pia , Näätsaari Laura , Kiuru Maija , Karhu Auli , Herva Riitta , Sallinen Satu-Leena , Vierimaa Outi , Björck Erik , Richard Stéphane , Gardie Betty , Bessis Didier , Glabeke Emmanuel Van , Blanco Ignacio , Houlston Richard , Senter Leigha , Hietala Marja , Aittomäki Kristiina , Aaltonen Lauri A. , Launonen Virpi , Lehtonen Rainer
Published: February 2011

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary tumor predisposition syndrome with fumarate hydratase (FH), which encodes a tricarboxylic acid cycle enzyme fumarase, as the predisposing gene. The HLRCC family members carry heterozygous germline mutations of the FH gene and the tumors often harbor a second hit making the growth fumarase deficient. The phenotype includes benign cutaneous and uterine leiomyomas as well as renal cell cancer (RCC). The HLRCC related RCCs usually belong to histological papillary type II subtype and are solitary, unilateral and aggressive. The benign leiomyomas are the most common manifestation of the syndrome affecting almost all FH mutation carriers whereas the renal cell cancer phenotype affects only about 20% of the HLRCC families. Interestingly, majority of the families with multiple renal cell cancer cases have concentrated in Finland and the U.S. Why the malignant phenotype affects only a part of the HLRCC patients is unknown. There is no genotype-phenotype correlation and type or site of the FH mutation does not affect the phenotype. The fumarase enzyme activity levels do not correlate with the phenotype either. Thus it is possible that the appearance of RCC requires, in addition to FH mutation, another genetic factor. To search for such a factor in four Finnish HLRCC families with multiple RCC cases we performed genome wide linkage and/or identical by descent (IBD) analyses. After finemapping procedures the only region compatible with linkage was the FH locus itself in 1q43. The genes of the region were screened but no pathognomonic mutations were found. Although these results do not exclude the existence of a genetic RCC risk modifier in HLRCC, the role of FH mutations behind RCC tumors is emphasized. Counseling and genetic testing should be available for HLRCC family members and the FH mutation carriers should be carefully followed up to enable early detection and treatment of the aggressive cancers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1844.
Abstract 1852: A novel role for the 185delAG BRCA1 mutant protein, BRAT, in ovarian cancer pathology
Authors: Linger Rebecca J. , Kruk Patricia A.
Published: February 2011

Objective: Familial history is the strongest risk factor for developing ovarian cancer (OC). Studying risk-associated BRCA1 truncation mutations, such as the founder mutation 185delAG, may reveal signaling pathways important in OC etiology. Normal human ovarian surface epithelial (HOSE) cells expressing the 185delAG mutant, BRAT, exhibit phenotypic changes due possibly in part to up-regulation of maspin, a tumor suppressor important in apoptosis, invasion, and metastasis that exhibits unique up-regulation in some cancer types. In the current study, we wish to determine BRAT's impact on expression and activity of matrix metalloprotease 1 (MMP1), another key player in invasion and metastasis, and the mechanism of this modulation.

Methods: HOSE, breast epithelial cells, and breast cancer cells transiently and stably expressing the 185delAG mutation were analyzed for differential target gene expression by semi-quantitative and real time PCR. SiRNA transfection was performed to achieve knockdown of c-Jun. Western blotting was used to evaluate MMP1 and c-Jun protein levels. FRET ELISA was performed on conditioned media to evaluate levels and functionality of secreted MMP1. Cells were treated with cisplatin and subjected to MTS assay to evaluate chemosensitivity.

Results: BRAT-expressing HOSE cells exhibited enhanced MMP1 mRNA expression. Higher levels of pro-MMP1 protein were detected by Western blotting of conditioned media. FRET ELISA revealed total MMP1 (pro and active forms) was also higher in BRAT-expressing cells, and that MMP1 in the conditioned media was functional. c-Jun knockdown diminished MMP-1 expression and secretion in HOSE. Expression of BRAT in normal breast and breast cancer cell lines failed to significantly alter chemosensitivity or MMP1 expression levels.

Conclusion: Normal HOSE cells expressing the BRAT mutation exhibit c-Jun-dependent changes in expression of MMP1. Further investigation is warranted to elucidate the mechanism of this change since increased expression of this gene may represent an initial step forward on the continuum of malignant transformation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1852.
Abstract 1856: A KRAS-variant as a putative biomarker of ovarian cancer risk
Authors: Weidhaas Joanne B. , Slack Frank
Published: February 2011

Purpose: Ovarian cancer is the single most deadly form of women's cancer, largely due to a lack of known risk factors or genetic markers. The KRAS oncogene and altered levels of the microRNA let-7 are associated with an increased risk of developing solid tumors. We investigated the association of a single nucleotide variant (rs61764370), referred to as the KRAS-variant, that disrupts a let-7 microRNA binding site in the KRAS oncogene 1, and ovarian cancer risk.

Methods: Specimens were obtained from non-selected ovarian cancer patients in three independent cohorts (n = 457) and two independent ovarian case-control studies. Specimens from ovarian cancer patients with hereditary breast and ovarian cancer (HBOC) syndrome (n = 58) and their family members were also collected.

Findings: The KRAS-variant is found in greater than 29% of non-selected ovarian cancer cases and is a marker for a significant increased risk of developing ovarian cancer by case control analysis (OR = 2.46, CI = 1.14-5.29, p = .020, n = 201). This was validated in a second independent ovarian case-control (n = 630). The KRAS-variant was also identified in 60% of HBOC patients without BRCA1 or BRCA2 mutations (n = 25, p < 0.001), previously considered uninformative, as well as in their family members with cancer.

Interpretation: These findings support the hypothesis that the KRAS-variant is a genetic marker of an increased risk of developing ovarian cancer, and suggests that the KRAS-variant may be a new biomarker of risk for HBOC families without other known genetic abnormalities.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1856.
Abstract 1862: Inactivation of P53 by HPV 16/18 E6 proteins in lung cancer is correlated with P53 codon 72 genotypes
Authors: Hsu Nan-Yung , Chen Chih-Yi , Chou Ming-Chih , Cheng Ya-Wen
Published: February 2011

A polymorphism at codon 72 of the p53 tumor suppressor gene is as a possible determinant for cancer risk and particularly carcinomas associated with HPV infection. Our recent report has shown that high-risk HPV 16/18 E6 proteins were associated with p53 protein degradation in lung cancer. To address the relationship of the different p53 genotypes and HPV oncoprotein expression in p53 protein degradation of lung cancer, 141 primary lung cancer patients were included in this study. PCR-RFLP, nested-PCR and immunohistochemial analysis were used to detect the p53 codon 72 polymorphism, HPV 16/18 infection, HPV 16/18 E6 and p53 protein expression. Our data showed that HPV 16/18 E6 protein but not HPV 16/18 DNA were reversely correlated with p53 expression, which was further confirmed by tissue in situ immunostaining. Additionally, the frequency of p53 protein negative expression in HPV 16/18 E6-positive/Arg homozygosity lung cancer tumors is much higher than that in the other three categorizes. This correlation was not found in HPV DNA infection. In conclusion, HPV 16/18 E6 proteins involvement in p53 inactivation to contribute to HPV-infected lung tumorigenesis is correlated with p53 codon 72 genotypes.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1862.
Abstract 1863: MutL homolog 1 promoter polymorphism in prostate cancer and benign prostatic hyperplasia
Authors: Tanaka Yuichiro , Liu Jan , Zaman Mohd S. , Majid Shahana , Saini Sharanjot , Chen Yi , Kawakami Kazumori , Dahiya Angela V. , Khatri Gaurav , Deng Guoren
Published: February 2011

MutL homolog (MLH1) is one of several DNA mismatch repair genes of which defects can result in mutation and genomic instability, and ultimately may lead to cancer. Polymorphisms of MLH1 promoter have been shown to be a risk for several types of cancers and thus, we hypothesize that MLH1 promoter polymorphisms can be a risk factor for prostatic diseases. To test this hypothesis, the genetic distribution of MLH1 polymorphism of the promoter region at nucleotide positions prior to translation start site at −1913 (rs34013758), −593 (rs34566456), −93 (rs1800734) and recently identified −107 (base change C to G) were analyzed in 131 normal healthy subjects, 134 benign prostatic hyperplasia (BPH), and 177 sporadic prostate cancer samples in a Japanese population by sequence-specific PCR and sequencing. These experiments show that the variant G/G genotype at the −93 location is associated with prostate cancer when compared to normal controls. Odds ratio and 95% confidence interval for cancer were 1.93 and 1.01-3.69, respectively, for the variant G/G genotype when compared to wildtype (A/A). Likewise, the variant G allele was associated as a risk for prostate cancer (P=0.063). However, no differences were observed for the promoter −93 polymorphism between BPH and controls as well as between stages or grades of prostate cancer. Interestingly, when analyzing the promoter −93 site with the Ile219Val (A to G) polymorphic site, a significant linkage was observed among controls (D’=1). Haplotype analysis showed bases A-A reflecting the wildtype forms for −93 and Ile219Val sites, respectively, to be significantly reduced in cancer compared to controls (P=0.033). The promoter −107 site was extremely rare with C/G type observed in one cancerous patient whereas rs34013758 and rs34566456 were not observed in this Asian population. This is the first report that demonstrates an association for the MLH1 promoter polymorphism with prostate cancer and these results are important in understanding its role in this disease.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1863.
Abstract 1868: Evaluation of the nucleotide excision repair polymorphisms for association with lung cancer risk
Authors: Buch Shama C. , Nukui Tomoko , Weissfeld Joel , Romkes Marjorie
Published: February 2011

There is increasing evidence that decreased nucleotide excision repair (NER) capacity may be associated with increased risk of cancer, including non-small cell lung cancer (NSCLC). We have studied the relationship of the NER pathway gene single nucleotide polymorphisms and haplotypes with NSCLC risk. Using a custom-designed Illumina GoldenGate assay 384 single nucleotide polymorphism (SNP) panel, we have screened for polymorphisms in nucleotide excision repair genes, cell cycle control genes, GSTP1 and ABCB1 and a set of ancestry informative markers in 797 Caucasian incident cases and 992 controls frequency matched for age (range 50-79) and gender. All subjects were ever smokers with a minimum 10 packyear smoking history. Our SNP selection strategy incorporates six SNP classes, i.e. haplotype tagSNPs defined by predicted LD scores; functional SNPs characterized by amino acid substitutions, SNPs that alter protein stability; evolutionary conservation across species; entromics and published epidemiological data. For the estimation of individual SNP and haplotype-specific associations with risk, unconditional logistic regression was used to estimate odds ratios and 95% confidence intervals in a dominant model adjusting for age, gender and packyear. A total of 26 unique SNPs in 14 genes were significantly associated with lung cancer risk. Haplotypes were reconstructed for each gene using HPlus and associations with risk were evaluated using the Cox proportional hazards model. The most frequent haplotype was used as the referent group for the estimation of hazard ratios (HR). Hazard ratios were calculated for common haplotypes i.e. those that were present at a frequency greater than 2% and were adjusted for age, gender and packyears. Among these 14 genes, 7 haplotypes were significant. These data suggest that NER pathway genotypes may serve to define an elevated risk subgroup. Supported in part by NIH 5P50 CA090440.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1868.
Abstract 1870: Genotype polymorphisms of DNA repair genes interact with estrogen exposure to breast cancer susceptibility
Authors: Cheng Chun-Wen , Yu Jyh-Cherng , Wang Hsiao-Wei , Hsiung Chia-Ni , Ding Shian-ling , Wu Pei-Ei , Wu Cheng-Wen , Shen Chen-Yang
Published: February 2011

Endogenous estrogen is suggested to initiate cell proliferation and cause oxidative DNA damage during breast tumorigenesis. Cells eliminate DNA damages by repair enzymes. Genotypic variants of DNA damage repair genes, participating base excision repair (BER) and nucleotide excision repair (NER) pathways, may act as modifiers that affect the association between estrogen exposure and breast cancer. In a hospital-based case-control study of female breast cancer, DNA samples from 401 cases and 533 healthy controls were enrolled among Chinese women in Taiwan. Genotyping polymorphisms of XRCC1 (Arg194Trp and Arg399Gln), OGG1 (Ser326Cys and Arg229Gln), ERCC2 Lys751Gln, ERCC4 Pro662Ser, and ERCC5 His1104Asp were determined and used to evaluate breast cancer susceptibility. Of these non-synonymous polymorphisms, ERCC5 1104Asp variant was significantly associated with breast cancer (OR=1.42; 95%CI=1.08-1.97), and this was more pronounced in women with prolonged estrogen exposure. A trend toward an increased risk of developing breast cancer was observed in women who carried greater numbers of combined high-risk genotypes of BER and NER genes (Ptrend = 0.038). The synergistic effect of multiple genes on risk elevation was significant in women having a longer period of estrogen exposure (>26 years), a longer menarche-to-FFTP interval (>11 years), greater age at the first full-term pregnancy (>26 years), and higher body mass index (>22) (all P<0.05). In conclusion, this study demonstrates that genotype polymorphisms for the DNA damage repair confer higher risk in individual susceptibility to endogenous estrogen on female breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1870.
Abstract 1871: Honokiol, a natural plant product, inhibits ultraviolet radiation-induced skin tumorigenesis in mice through inhibition of inflammation and inflammatory mediators
Authors: Sharma Som D. , Vaid Mudit , Katiyar Santosh K.
Published: February 2011

Chronic exposure of solar ultraviolet (UV) radiation is the major etiologic agent for over one million new cases of non-melanoma skin cancers in the US each year. These cutaneous malignancies thus have a tremendous impact on public health and healthcare expenditures. The use of natural plant products has received considerable interest to protect skin from adverse biological effects of UV radiation since the protective clothing and use of sunscreens are not adequate for skin photoprotection. The photoprotective effect of honokiol, a plant product from Magnolia species, therefore assessed using SKH-1 hairless mouse model. To determine the skin cancer chemopreventive effect and associated mechanism of honokiol, a hydrophilic cream based topical formulation was developed. Different groups of mice (n=20) treated with or without honokiol were subjected to photocarcinogenesis protocol. Mice were irradiated to UVB (180 mJ/cm2) three times a week. At the termination of the experiment at 24th week, we found that topical application of honokiol (1mg & 3mg/mouse) inhibited UVB-induced skin tumor development in terms of tumor incidence (10-20%), tumor multiplicity (40-60%) and tumor size (50-75%). Since UV-induced inflammation plays a crucial role in the development of skin tumors, we examined the effect of honokiol on UVB-induced biomarkers of inflammation, such as the expression levels of cyclooxygenase-2 (COX-2), prostaglandins (PG), proliferating cell nuclear antigen (PCNA), infiltration of inflammatory leukocytes, development of edema and epidermal hyperplastic response using immunostaining, western blotting and RT-PCR. Our data revealed that topical application of honokiol before each exposure of UVB radiation resulted in a dose-dependent inhibition of UVB-induced expression of COX-2, PGE2, developments of edema and infiltration of leukocytes at the UVB-irradiated skin sites. Honokiol also inhibited the levels of PCNA (hyperplastic potential) in epidermal keratinocytes of UVB-exposed skin. The inhibitory effects of honokiol on inflammatory mediators were also found in skin tumor samples. The results of this study suggest that honokiol has the ability to inhibit UVB radiation-induced skin tumor development in mice and it is associated with the inhibition of UVB-induced inflammation and inflammatory mediators in mouse skin and skin tumors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1871.
Abstract 1872: Treatment of colon cancer with black raspberries reduces DNA Methyltransferase 1-associated gene methylation
Authors: Seguin Claire M. , Huang Yi-Wen , Huang Tim , Yang Guang-Yu , Arnold Mark , Martin Edward , Sardo Christine , Stoner Gary D. , Wang Li-Shu
Published: February 2011

Black raspberries (BRB) confer anti-cancer effects in gastrointestinal organs via a number of mechanisms. Recently, we have shown that BRB are capable of reversing aberrant promoter-region methylation and silencing of tumor suppressor genes in colorectal cancers in two separate clinical trials. Familial adenomatous polyposis (FAP) is characterized by inherited mutation of the APC gene resulting in uncontrolled growth of pre-cancerous polyps and 100% risk of colon cancer by age 40. In a 9-month clinical trial, a total of fourteen FAP patients were treated with two 700 mg BRB suppositories intra-rectally once a day. Seven of the 14 patients consumed a slurry containing 20g freeze-dried BRB powder three times a day while the other seven received a placebo slurry. In the second study, twenty-five colorectal cancer patients consumed a slurry containing 20g of BRB powder three times a day for a short period (2-4 weeks) before surgery. DNA from both studies was extracted from paraffin-embedded biopsies of normal and tumor tissue before and after treatment. Methylation status of the promoter regions of tumor suppressor genes were studied using MassARRAY/EpiTyper which quantifies the percent methylation of C-G units (each containing 1-3 CpGs) in target gene promoter regions The five genes studied, including p16, a cell cycle regulator, PAX6a, a development regulator, and three Wnt pathway inhibitors, SFRP2, SFRP5 and WIF1, were all positively regulated by BRB in colon tumors, however, only p16, SFRP2 and WIF1 were demethylated in rectal polyps from FAP patients. In both studies, 75% of both normal and tumor tissues showed decreased methylation of at least one tumor suppressor gene. Multiple-gene demethylation was different in the two studies. More than one gene was found to be reduced in methylation in a greater percentage of colon tumors (55%) than in normal tissues (26%) from colon cancer patients. In contrast, in the FAP study, more than one gene was demethylated in a greater percentage of normal tissue (23%) than in polyps (7%). However, the effect of BRB on the expression of DNA Methyltransferase 1 (DNMT1), a maintenance methylation enzyme, was similar in both colon cancers and polyps from FAP patients. In both FAP and colon cancers, demethylation of at least one gene coincided with DNMT1 decrease in a greater percentage of tumor tissues (63%, 79%) than in normal tissues (20%, 50%), respectively. This correlation suggests that in both polyps from FAP patients and in colon cancers, BRB action on methylation acts through DNMT1 reduction to a greater extent in tumor tissue than in normal tissue.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1872.
Abstract 1877: Involvement of mitochondrial respiratory complexes in capsaicin mediated ROS generation and apoptosis in pancreatic cancer cells
Authors: Pramanik Kartick C. , Boreddy Srinivas Reddy , Kandala Prabodh K. , Srivastava Sanjay K.
Published: February 2011

Capsaicin (N-vanillyl-8-methyl-nonenamide) is a homovanillic acid derivative and the spicy component of chili pepper. In our previous study, we have shown that capsaicin induced apoptosis in pancreatic cancer cells was associated with the generation of ROS and persistent disruption of mitochondrial membrane potential. However, the exact mechanism by which capsaicin causes ROS generation and cell death was not fully clear. We now evaluated the effect of capsaicin on mitochondrial respiratory complexes and ROS generation. The generation of ROS was about 3 fold and as early as 2h after capsaicin treatment in BxPC-3 cells and inhibited by rotenone and antimycin-A but not by 4-nitropropionic acid or sodium azide. Rotenone, 4-nitropropionic acid, antimycin A and sodium azide are the inhibitors of NADH-ubiquinone oxidoreductase (Complex I), succinate ubiquinone oxidoreductase (Complex II), ubiquinol cytochrome c reductase (Complex III) and cytochrome c oxidase (Complex IV) respectively. To further delineate the mechanism of ROS generation, effect of capsaicin was evaluated on the enzymatic activities of above-mentioned mitochondrial complexes in BxPC-3 cells. Our results show that capsaicin treatment significantly reduced complex I and complex III enzymatic activities suggesting the involvement of mitochondrial complex I and III in capsaicin mediated ROS generation. Capsaicin however did not affected complex II or complex IV activities. Our results further revealed that about 3 fold apoptosis induced by capsaicin in BxPC-3 cells was inhibited by rotenone and antimycin-A. Moreover, capsaicin mediated release of cytochrome c and AIF and cleavage of caspase-9 and caspase-3 were significantly inhibited by rotenone and antimycin-A. On the other hand, catalase or EUK (a mimetic of catalase) pretreatment block capsaicin-mediated ROS generation and apoptosis. Taken together, our results suggest the involvement of mitochondrial complex I and III in capsaicin mediated ROS generation and apoptosis. [Supported in part by RO1 grants CA 106953 and CA129038 (to SKS) awarded by National Cancer Institute].

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1877.
Abstract 1878: Dietary intake of pterostilbene, a constituent of blueberries, inhibits the β-catenin/p65 downstream signaling pathway and colon carcinogenesis in rats
Authors: Paul Shiby , DeCastro Andrew , Lee Hong Jin , Smolarek Amanda K. , So Jae Young , Simi Barbara , Wang Chung Xiou , Zhou Renping , Rimando Agnes M. , Suh Nanjoo
Published: February 2011

Stilbenes are phytochemicals present in grapes, berries, peanuts and red wine. A widely studied stilbene, resveratrol (trans-3,5,4’-trihydroxystilbene), has been shown to exert anti-oxidant, anti-inflammatory, chemopreventive, and anti-aging effects in a number of biological systems. Recently, pterostilbene (trans-3,5-dimethoxy-4’-hydroxystilbene), a structurally related stilbene found in blueberries, has been shown to exhibit significant effects against cell proliferation, inflammation, invasion and metastasis in various models. We reported earlier that pterostilbene was effective in reducing the incidence and multiplicity of aberrant crypt foci (ACF) formation in the colon of rats injected with the carcinogen, azoxymethane (AOM). Our present study was to identify the chemopreventive potential of pterostilbene with colonic tumor formation as an end point, and further to evaluate the mechanistic action of pterostilbene during colon carcinogenesis. F344 rats were given two AOM injections subcutaneously when they were 7 and 8 weeks old, and continuously fed the control or 40 ppm pterostilbene diet for 45 weeks. Overall analyses indicated that pterostilbene reduced colon tumor multiplicity of non-invasive adenocarcinomas, lowered a cell proliferation marker, proliferating cell nuclear antigen (PCNA), and down-regulated the expression of β-catenin and cyclin D1. Pterostilbene decreased mucosal levels of the pro-inflammatory cytokines TNF-α, IL-1β and IL-4. Colon tumors from pterostilbene fed animals showed reduced expression of the inflammatory enzymes iNOS and COX-2, as well as nuclear staining for phospho-p65, a key molecule in the NF-κB pathway. In cell culture studies using HT-29 cells, pterostilbene reduced the protein levels of β-catenin, cyclin D1 and c-MYC, altered the cellular localization of β-catenin, and inhibited the phosphorylation of p65. Our data with pterostilbene in suppressing colon tumorigenesis, cell proliferation as well as key inflammatory markers in vivo and in vitro suggest the potential use of pterostilbene for colon cancer prevention.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1878.