bluuebunny/crossref_metadata_2025 huggingface dataset:
AIB1:ERα Transcriptional Activity Is Selectively Enhanced in Aromatase Inhibitor–Resistant Breast Cancer Cells
Authors: O'Hara Jane , Vareslija Damir , McBryan Jean , Bane Fiona , Tibbitts Paul , Byrne Christopher , Conroy Ronán M. , Hao Yuan , Gaora Peadar Ó , Hill Arnold D.K. , McIlroy Marie , Young Leonie S.
Published: May 2012

Purpose: The use of aromatase inhibitors (AI) in the treatment of estrogen receptor (ER)-positive, postmenopausal breast cancer has proven efficacy. However, inappropriate activation of ER target genes has been implicated in the development of resistant tumors. The ER coactivator protein AIB1 has previously been associated with initiation of breast cancer and resistance to endocrine therapy.

Experimental Design: Here, we investigated the role of AIB1 in the deregulation of ER target genes occurring as a consequence of AI resistance using tissue microarrays of patients with breast cancer and cell line models of resistance to the AI letrozole.

Results: Expression of AIB1 associated with disease recurrence (P = 0.025) and reduced disease-free survival time (P = 0.0471) in patients treated with an AI as first-line therapy. In a cell line model of resistance to letrozole (LetR), we found ERα/AIB1 promoter recruitment and subsequent expression of the classic ER target genes pS2 and Myc to be constitutively upregulated in the presence of both androstenedione and letrozole. In contrast, the recruitment of the ERα/AIB1 transcriptional complex to the nonclassic ER target cyclin D1 and its subsequent expression remained sensitive to steroid treatment and could be inhibited by treatment with letrozole. Molecular studies revealed that this may be due in part to direct steroid regulation of c-jun-NH2-kinase (JNK), signaling to Jun and Fos at the cyclin D1 promoter.

Conclusion: This study establishes a role for AIB1 in AI-resistant breast cancer and describes a new mechanism of ERα/AIB1 gene regulation which could contribute to the development of an aggressive tumor phenotype. Clin Cancer Res; 18(12); 3305–15. ©2012 AACR.
Combination of an Allosteric Akt Inhibitor MK-2206 with Etoposide or Rapamycin Enhances the Antitumor Growth Effect in Neuroblastoma
Authors: Li Zhijie , Yan Shuang , Attayan Navid , Ramalingam Sridevi , Thiele Carol J.
Published: May 2012

Purpose: Activation of Akt is a marker of decreased event-free or overall survival in neuroblastoma patients. MK-2206, a novel allosteric Akt inhibitor, is now tested in clinical trials in adult cancers. In this study, effect of MK-2206 on tumor growth and murine survival, alone or in combination, with etoposide or rapamycin was evaluated.

Experimental Design: The anticell proliferation effect of MK-2206 was tested in eight neuroblastoma cell lines by MTS assay. Caspase-3/7 activity, cell-cycle analysis, and reactive oxygen species (ROS) production were determined. Effect of MK-2206 combined with etoposide or rapamycin was evaluated in vitro and in vivo. Akt phosphorylation was measured by Western blotting in neuroblastoma cells and tumors.

Results: In vitro, MK-2206 treatment inhibited neuroblastoma cell proliferation, which was accompanied by a cell line selective G1 arrest of cell cycle or production of ROS. A synergistic effect between MK-2206 and etoposide was detected in four tested neuroblastoma cell lines via caspase-dependent apoptosis, whereas increased inhibition of cell growth induced by combination of MK-2206 and rapamycin was mediated by ROS production. In vivo, MK-2206 alone decreased tumor growth and increased murine survival at dose that inhibited Akt phosphorylation in tumors. MK-2206, in combination with etoposide or rapamycin, caused a significant decrease in tumor growth and increase of murine survival compared with MK-2206 alone.

Conclusion: Akt inhibition by MK-2206 increased the efficacy of etoposide or rapamycin. Our study supports future clinical evaluation of MK-2206 in combination with conventional cytotoxic therapy or with rapamycin in high-risk neuroblastoma patients. Clin Cancer Res; 18(13); 3603–15. ©2012 AACR.
The Proteasome Activator PA200 Regulates Tumor Cell Responsiveness to Glutamine and Resistance to Ionizing Radiation
Authors: Blickwedehl Jennifer , Olejniczak Scott , Cummings Ryan , Sarvaiya Nilofar , Mantilla Ana , Chanan-Khan Asher , Pandita Tej K. , Schmidt Marion , Thompson Craig B. , Bangia Naveen
Published: May 2012

The cellular response to ionizing radiation (IR) involves a variety of mechanisms to repair damage and maintain cell survival. We previously reported that the proteasome activator PA200 promotes long-term cell survival after IR exposure. The molecular function of PA200 is to enhance proteasome-mediated cleavage after glutamate; however, it is not known how this molecular function promotes survival after IR exposure. Here, we report that upon IR exposure, cellular demand for exogenous glutamine is increased. Cells containing PA200 are capable of surviving this IR-induced glutamine demand, whereas PA200-deficient cells show impaired long-term survival. Additional glutamine supplementation reverses the radiosensitivity of PA200-knockdown cells suggesting impaired glutamine homeostasis in these cells. Indeed, PA200-knockdown cells are unable to maintain intracellular glutamine levels. Furthermore, when extracellular glutamine is limiting, cells that contain PA200 respond by slowing growth, but PA200-knockdown cells and cells in which post-glutamyl proteasome activity is inhibited are nonresponsive and continue rapid growth. This cellular unresponsiveness to nutrient depletion is also reflected at the level of the mTOR substrate ribosomal S6 kinase (S6K). Thus, inability to restrict growth causes PA200-deficient cells to continue growing and eventually die due to lack of available glutamine. Together, these data indicate an important role for PA200 and post-glutamyl proteasome activity in maintaining glutamine homeostasis, which appears to be especially important for long-term survival of tumor cells after radiation exposure. Mol Cancer Res; 10(7); 937–44. ©2012 AACR.
Abstract A10: Gene expression analysis of malignancy associated changes in normal bronchial epithelium
Authors: Thu Kelsie , Campbell Jennifer , Garnis Cathie , Coe Bradley , Lam Wan , MacAulay Calum , Lam Stephen
Published: May 2012

A10

Background

Lung cancer is the number one cancer-related cause of death in the world. The poor prognosis for lung cancer patients is largely due to the lack of an effective non-invasive method to detect the disease in its early stage. Using quantitative nuclear morphometry of sputum cells, we have previously demonstrated that in the presence of tumour, cytologically normal appearing diploid cells may exhibit malignancy-associated changes (MACs) and that these changes may be used as surrogate markers for early detection. The molecular basis for MACs is not known.

Objective

Our objective is to identify malignancy-associated gene expression changes in normal bronchial epithelial cells obtained by bronchial brushing.

Methods

We compared the pre- and post-surgical resection gene expression profiles of bronchial epithelial cells obtained by brushing of airways in the lung opposite to the one containing the lung cancer. Agilent whole genome expression arrays were used to generate mRNA transcript profiles for seven paired normal bronchial brushings taken before and 3 to 6 months after surgical resection of the tumour. Ingenuity Pathway Analysis software was used to identify downstream expression targets of the soluble signaling factors VEGF, TGF-β, TNF-α, and IL-8, which have been reported to be secreted by lung tumour cells. The target genes identified were analyzed for malignancy induced differential gene expression between normal bronchial epithelial cells from cancerous and non-cancerous environments.

Results

We detected differential expression of multiple target genes in the bronchial brush cells. Genes that were found to be differentially expressed included downstream targets of the signaling molecules EGF,TGF-β, and VEGF.

Conclusion

Soluble signaling molecules secreted by lung malignancies induce MACs, as evident by altered gene expression after removal of the tumour. Although further investigation is necessary, our results are consistent with previous observation that lung tumours can induce MACs in normal appearing bronchial cells in the vicinity of the tumor. MACs may be a potential marker for early detection of lung cancer. This data also provides evidence that MACs can be measured quantitatively in bronchial brush cells using gene expression analysis.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A10.
Abstract A103: Risk of breast cancer with plasma prolactin concentrations by phosphorylated STAT3 and STAT5 status
Authors: Tworoger Shelley , Rice Megan , Belsley Nichole , Walker Sarah , Collins Laura , Hankinson Susan , Frank David
Published: May 2012

A103

Prolactin, a lactogenic hormone, has been associated with risk of breast cancer in premenopausal and postmenopausal women. Prolactin may act by influencing transcription factors in the Signal Transducer and Activator of Transcription (STAT) pathway. In particular, STAT3 and STAT5 appear to be important in breast carcinogenesis; prolactin is known to activate STAT5 via phosphorylation. To determine whether prolactin may act through STAT signaling, we examined whether prediagnostic prolactin levels were differentially associated with risk of breast tumors based on their expression of phosphorylated STAT3 (pSTAT3) and STAT5 (pSTAT5). Tissue microarrays (TMAs) were constructed from 3,093 breast cancers from women enrolled in the Nurses Health Study. Of these, 443 cases had matching plasma prolactin levels drawn at diagnosis; one or two controls were matched to each case by age, menopausal status/hormone use, and characteristics of the blood draw. Immunohistochemical studies with pSTAT3 and pSTAT5 were performed on the TMAs. Tissue cores were scored from 0-3 based on intensity and quantity of nuclei staining. Relationships between expression of pSTAT3 or pSTAT5 and clinicopathologic features were examined by Chi-squared tests. Polytomous logistic regression was used to evaluate the relationship between prolactin and risk of breast tumors by staining expression, adjusting for matching factors and breast cancer risk factors. Interpretable tissue cores were available for 309 subjects. Of these, 195 (63%) and 114 tumors (37%) showed negative/weak (0-1) and moderate/strong staining (2-3) respectively for pSTAT3. 178 (58%) and 131 (42%) tumors showed negative/weak and moderate/strong staining respectively for pSTAT5. Absence of expression of pSTAT3 was significantly associated with high grade (p=0.04) and invasiveness (p=0.04). Though not statistically significant, pSTAT3- status also was associated with lymph node involvement and larger tumor size. pSTAT5 was not associated with other tumor characteristics. Prolactin levels were similarly associated with pSTAT3+ (RR, top vs. bottom quartile=1.7, 95% CI=1.1-2.8) and pSTAT3- tumors (comparable RR=1.8, 95%CI=1.0-3.3). However, high versus low prolactin levels were more strongly associated with pSTAT5+ tumors (RR=2.3, 95%CI=1.3-4.2) compared to pSTAT5- tumors (RR=1.5, 95%CI=0.9-2.4), although the p-heterogeneity was not statistically significant (p=0.28). Our findings suggest that prolactin may influence breast cancer risk via activation of STAT5. On-going analyses are exploring the combined role of pSTAT3 and pSTAT5 presence as well as other hormones thought to modulate or reflect STAT activity including IGFs, CRP, and adiponectin.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A103.
Abstract A106: Serum testosterone concentrations and risk of testicular germ cell tumors
Authors: Chia Victoria , Quraishi Sabah , Graubard Barry , Stanczyk Frank , Rubertone Mark , Erickson Ralph , McGlynn Katherine
Published: May 2012

A106

Although the incidence of testicular germ cell tumors (TGCT) has been rising worldwide, little known about the etiology. There is evidence, however, that TGCT is related to other male reproductive disorders, specifically, hypospadias, cryptorchidism and infertility. Because testosterone is responsible for the development and proliferation of testicular cells and testicular descent, it is plausible that testosterone and its binding protein, sex hormone binding globulin (SHBG), may be associated with TGCT risk. Using 512 case and 789 control participants from the U.S. Servicemen’s Testicular Tumor Environmental and Endocrine Determinants (STEED) Study, we assessed associations of pre-diagnostic serum SHBG and testosterone (measured total and calculated free) concentrations and risk of TGCT. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using adjusted logistic regression models. Among the controls, SHBG concentrations increased with age (p<0.01), while free testosterone concentrations decreased with age (p=0.02). Total testosterone concentrations, however, were not associated with age (p=0.84). SHBG and total testosterone concentrations decreased with increasing body mass index (p<0.01), however free testosterone did not (p=0.67). Overall, there were no statistically significant associations between SHBG and total testosterone concentrations and TGCT risk. There were suggestions that men had an increased risk of TGCT if they were in the highest quintile of SHBG (OR=1.41, 95% CI, 0.98-2.02) and free testosterone (OR=1.31, 95% CI, 0.91-1.88), but there were no statistically significant trends. Serum total testosterone concentrations were not associated with TGCT risk. There did not appear to be differences in risk by tumor subtype, seminoma versus nonseminoma, nor effect modification by body mass index. These results suggest that serum testosterone is not associated with risk of TGCT; other endogenous hormones, however, such as gonadotropins and estrogens, may provide additional clues to the etiology of TGCT.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A106.
Abstract A109: A prospective study of vitamin D receptor polymorphisms, interaction with vitamin D status, and colorectal cancer risk in men
Authors: Lee Jung Eun , Li Haojie , Giovannucci Edward , Hollis Bruce , Hunter David , Lee I-Min , Stampfer Meir , Ma Jing
Published: May 2012

A109

Growing evidence suggests an elevated risk of colorectal cancer among individuals with low levels of vitamin D, the biological actions of which is mediated by the vitamin D receptor (VDR). We examined the prospective associations between three VDR single nucleotide polymorphisms (SNPs) (BsmI (bb, bB/BB), FokI (FF, Ff/ff), and Cdx2 (G>A)) and colorectal cancer risk and their interactions with plasma vitamin D status in a nested case-control study among men in the Physicians’ Health Study. A total of 249 incident colorectal cancer cases were identified through 2000 among men who provided blood specimens in 1982-1984 and individually matched to controls by age and smoking. We used conditional logistic regression to calculate the relative risk (RR) and 95% confidence interval (95% CI). We found that men with the VDR Cdx2 variant A allele tended to have a lower risk of developing colorectal cancer compared to men with the homozygous GG genotype (RR=0.71; 95% CI = 0.50-1.02; P = 0.06). Moreover, the lower risk of colorectal cancer associated with the VDR Cdx2 A genotype was mainly confined to men with low vitamin D status (plasma 25(OH)D below median level; RR = 0.45; 95% CI = 0.24-0.84; P = 0.03) but not among men with vitamin D levels above the median (P for interaction = 0.04). We found no statistically significant associations for the other two VDR SNPs, FokI or BsmI, or statistically significant interactions between plasma 25(OH)D levels and these two SNPs. Our prospective data suggest the hypothesis that the functional polymorphic Cdx2 A allele variation in the VDR gene, which is linked to a higher transcriptional activity of the VDR, may be protective against colorectal cancer development when vitamin D status is low.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A109.
Abstract A110: Kinase gene expression profiles are associated with clinical outcomes in clear cell renal cell carcinoma patients
Authors: Hildebrandt Michelle , Tamboli Pheroze , Huang Maosheng , Ye Yuanqing , Lee Ju-Seog , Wu Xifeng
Published: May 2012

A110

There are 516 known kinases in the human genome. These proteins are involved in regulating nearly all cellular processes through phosphorylation of target proteins. Because of their important role maintaining proper cellular function, they are often misregulated during tumorigenesis and associated with clinical outcomes in cancer patients. Similarly to other cancers, several kinases have been found to play key roles during development of renal cell carcinoma (RCC). However, less is known about the global expression status of these genes in RCC and their association with clinical outcomes. To identify variation in the RCC kinome, we performed a systematic analysis of gene expression for 503 human kinases using Illumina whole genome arrays in 93 tumor samples. Expression levels were analyzed with regard to associations with recurrence and overall survival. Six kinases were found to be significantly associated with an increased risk developing a recurrence, while two kinases were protective (p < 0.01). Furthermore, an expression signature comprised of these eight genes was able to identify low risk and high risk groups of patients (HR: 26.83, 95% CI: 3.77-190.78, p = 0.0010). These two risk groups also had significantly different recurrence-free survival times of 67.6 compared to 37.9 months (p = 0.0003) for the low and high risk groups, respectively. Expression of one of these eight genes, IKBKE, was also associated with a 5.3-fold increased risk of dying (95% CI: 1.93-14.59, p = 0.0012). Interestingly, this kinase was constantly associated with a poor prognosis in both univariable and multivariable analyses with similar HRs, indicating that expression levels of this gene may be a candidate, independent prognostic marker for RCC. IKBKE is a member of the NFκB signaling pathway and is responsible for regulation of NFκB-mediated transcriptional activation of genes involved in inflammation, immunity and stress responses. Overall, these results suggest a major role of global kinase gene expression in modulating clinical outcomes in RCC patients while identifying several candidate genes, including IKBKE, for further study.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A110.
Abstract A111: Genetic variations in five estrogen metabolizing genes and endometrial cancer risk
Authors: Yang Hannah , Platz Elizabeth , Gaudet Mia , Lacey James , Brinton Louise , Lissowska Jolanta , Peplonska Beata , Sherman Mark , Chanock Stephen , Garcia-Closas Montserrat
Published: May 2012

A111

BACKGROUND

Estrogen plays a major role in endometrial carcinogenesis and the balance of estrogen metabolites has been hypothesized to be a determinant of risk. Cytochrome p450 (CYP) enzymes, CYP1A1, CYP1A2, and CYP3A4 catalyze the 2-OHE1 pathway, whereas the CYP1B1 catalyzes the 4-OHE1 pathway. The activity of these enzymes determines the proportion of metabolites and a higher proportion of the 4-OHE1 metabolites is thought to have a higher carcinogenic potential. Although several studies have examined the association between single nucleotide polymorphisms (SNPs) of these estrogen metabolizing genes and endometrial cancer risk, results have been inconsistent and limited to putatively functional variants.

METHODS

We comprehensively assessed known common genetic variation in these estrogen metabolizing genes by genotyping candidate and tagging SNPs (tagSNPs) in a population-based case-control study of 417 endometrial cancer cases and 407 controls (most of whom were postmenopausal) conducted in Poland (Warsaw and Lodz) between 2001-2003. The following criteria were used to identify tagSNPs: (1) located in the respective gene or within the 5kb flanking regions, (2) with a minor allele frequency greater than or equal to 0.01 in Caucasian populations, and (3) with pairwise r2=0.90 between tagSNPs and undetermined SNPs. A total of 5 SNPs for CYP1A1, 7 for CYP1A2, 9 for CYP1A1/A2, 34 for CYP1B1, 6 for CYP3A4, and 12 for COMT were examined. Genotyping was performed using an Illumina Custom Infinium iSelect assay that included nearly 27,000 SNPs with coverage of over 1,300 candidate genes.

RESULTS

We did not observe significant associations for candidate variants of CYP1A1 (rs1048943 (I462V) per C allele: OR (95% CI)=0.98 (0.56-1.72); rs1799814 (T461N) per T allele: 1.75 (0.94-3.24)); CYP1A2 (rs762551 (IVS1-154C>A) per C allele:0.91(0.74-1.12)); CYP1B1 (rs1056827 (A119S) per A allele: 0.98 (0.80-1.20); rs1056836 (V432L) per C allele: 0.96 (0.79-1.18); rs1800440 (N453S) per C allele: 1.15 (0.88-1.51)); and CYP3A4 (rs2740574 (-391A>G) per C allele: 1.46 (0.84-2.54)). In addition, we did not observe any significant association with endometrial cancer risk in haplotype analyses (global p-value>0.3) or the individual tagSNPs analyses (p-trend>0.09). Meta-analysis including our study and previous reports for these SNPs did not show significant overall associations; however, there is substantial heterogeneity across studies.

DISCUSSION

Our findings do not provide evidence for a substantial association between common genetic variation of estrogen metabolizing genes with endometrial cancer risk. However weak associations with these genes or association with other genes in the estrogen metabolizing pathway may exist.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A111.
Abstract A114: No increased risk of cancer after coal tar treatment in patients with psoriasis or eczema
Authors: Roelofzen Judith , Aben Katja , Oldenhof Ursula , Coenraads Pieter-Jan , Alkemade Hans , Van de Kerkhof Peter , Van der Valk Pieter , Kiemeney Lambertus
Published: May 2012

A114

Background

Coal tar is an effective topical treatment for psoriasis and eczema, but it contains several carcinogenic polycyclic aromatic hydrocarbons (PAHs), such as benzo(a)pyrene, benz(a)antracene and dibenz(a,h)anthracene. Occupational and animal studies showed an increased risk of cancer after exposure to coal tar. Many dermatologists have abandoned this effective treatment for safety reasons, although the risk of cancer after dermatological coal tar therapy is unclear. To study the risk of cancer after coal tar treatment and other therapies, the LATER study (Late effects of coal tar treatment in eczema and psoriasis; the Radboud study) was conducted.

Methods

A large historical cohort study was performed including 13,200 patients diagnosed with psoriasis and eczema between 1960 and 1990 at three large hospitals in the Netherlands. Specific information on skin disease and treatment, risk factors and cancer occurrence was retrieved from medical files, postal questionnaires, the Netherlands Cancer Registry and Causes of Death Registry. Cox Proportional Hazard regression models were used to evaluate differences in cancer risk by treatment modality.

Results

Coal tar treatment did not increase the risk of non-skin malignancies (HR=0.92; 95%CI=0.78-1.09), nor the risk of skin cancer (excluding basal cell carcinoma) (HR=1.09; 95%CI=0.69-1.72). Alternative therapies, such as PUVA and systemic therapies appeared to be associated with an increased risk of skin cancer (HR=1.17; 95%CI=0.75-1.82 and HR=2.33; 95%CI=1.60-3.40, respectively), but no increased risk of non-skin cancer was observed (HR=0.91; 95%CI=0.75-1.10 and HR=1.12; 95%CI=0.95-1.32).

Conclusion

This study is the first study with sufficient numbers of patients and follow-up to reliably estimate the risk of cancer after coal tar treatment. The use of coal tar was not associated with an increased risk of cancer. PUVA and systemic therapies showed an increased risk of skin cancer, but no increased risk of tumours at other sites was observed. After considering the risks and benefits of coal treatment against the risks and benefits of other therapies, we conclude that coal tar coal tar can be maintained as a safe and effective treatment within dermatological practice.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A114.
Abstract A12: Increased expression of STEAP1 gene as potential poor prognostic marker of prostate cancer
Authors: Ihlaseh Shadia , Gambarini Greicy , Trindade Jose Carlos , Domingues Maria , Rogatto Silvia , de Camargo Joao Lauro
Published: May 2012

A12

Prostate cancer is a public health problem due to its high incidence and mortality rates. STEAP1 and STEAP2 genes (six-transmembrane epithelial antigen of prostate 1 e 2) are mapped at 7q21.13 region, where we have previously described genomic gains by array comparative genomic hybridization (aCGH) of primary prostate adenocarcinomas (PCa). The involvement of these genes in PCa development and progression remains to be clarified. They express tumor antigens and are putative molecular markers. The objective of this study was to determine STEAP1 and STEAP2 genes expressions by real time quantitative PCR (qPCR) and STEAP1protein expression by immunohistochemistry in samples of PCa, in surrounding non-neoplastic tissues, and in prostate nodular hyperplasia. Patients were classified in three groups of recurrence risk depending on serum PSA levels, Gleason scores, and tumor stages for qPCR analysis. Increased STEAP1 and STEAP2 genes expressions were registered in 16% and 21% of the 55 samples, respectively; both genes presented simultaneous increased expression in three high-risk cases. Similar pattern of expression of these genes were detected in the majority of PCa and in surrounding non-neoplastic tissues. Compared to surrounding non-neoplastic tissues, there was significant increase of STEAP1 expression in tumor samples with Gleason scores ≥ 7(4+3) and in cases with vascular invasion. There was a trend for increased STEAP1 expression in high-risk cases when compared to the moderate-risk group. In accordance with gene expression, higher levels of STEAP1 protein were expressed in PCa compared to surrounding non-neoplastic tissues. Our data suggest that increased STEAP1 expression is related to clinical and pathological parameters of PCa patients and it use as a poor prognostic marker should be considered.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A12.
Abstract A120: Agricultural pesticide use and pancreatic cancer risk in the agricultural health study cohort
Authors: Andreotti Gabriella , Beane Freeman Laura , Hou Lifang , Coble Joseph , Rusiecki Jennifer , Hoppin Jane , Silverman Debra , Alavanja Michael
Published: May 2012

A120

Pancreatic cancer is a rapidly fatal disease that has been linked with pesticide use. Previous studies have reported excess risks of pancreatic cancer with organochlorines such as DDT, however, many other commonly used pesticides have not been examined. To further examine the potential associations between the use of a number of pesticides and pancreatic cancer, we conducted a case-control analysis in the Agricultural Health Study, one of the largest prospective cohorts with over 89,000 participants including pesticide applicators and their spouses in Iowa and North Carolina. This analysis included 93 incident pancreatic cancer cases (64 applicators, 29 spouses) and 82,503 cancer-free controls who completed an enrollment questionnaire providing detailed pesticide use, demographic and lifestyle information.Ever use of 24 pesticides and intensity-weighted lifetime days [(lifetime exposure days) x (exposure intensity score)] of 13 pesticides was assessed. Risk estimates were calculated using unconditional logistic regression controlling for age, smoking, and diabetes. Among pesticide applicators, two herbicides (EPTC and pendimethalin) of the 13 pesticides examined for intensity-weighted lifetime use showed a statistically significant exposure-response association with pancreatic cancer. Applicators in the top half of lifetime pendimethalin use had a 3.0-fold (95% CI 1.3-7.2, p-trend=0.01) risk compared to never users, and those in the top half of lifetime EPTC use had a 2.56-fold (95% CI=1.1-5.4, p-trend=0.01) risk compared to never users. Organochlorines were not associated with an excess risk of pancreatic cancer in this study. These findings suggest that herbicides, particularly pendimethalin and EPTC, may be associated with pancreatic cancer.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A120.
Abstract A123: Serum levels of hormones and breast tissue composition in young women
Authors: Martin Lisa , Chavez Sofia , Gunasekara Anoma , Salleh Ayesha , Melnichouk Olga , Yaffe Martin , Minkin Salomon , Bronskill Michael , Boyd Norman
Published: May 2012

A123

Background

Percent mammographic density (PMD) is a strong and heritable risk factor for breast cancer with characteristics that suggest it may be a marker of susceptibility to the disease. We have examined serum hormone levels and other factors associated with breast tissue composition in young women, when susceptibility to breast carcinogens is greatest.

Methods

In 400 young women aged 15-30 years we obtained quantitative measures of breast water, which reflects fibro-glandular tissue, and breast fat using magnetic resonance (MR), and collected anthropometric and other data. All examinations were performed in the follicular phase of the menstrual cycle and fasting blood samples for hormone assays were obtained on the morning of the MR examination.

Results

Serum levels of growth hormone (GH) and sex hormone binding globulin (SHBG) were positively associated with percent breast water content in all young women aged 15-30, and the associations remained statistically significant after adjustment for height, weight and other covariates. IGF-I was not associated with any MR breast measures. Serum levels of estradiol, progesterone, and testosterone, were not associated with MR breast measures in all young women, or in those aged 20-30, but did show evidence of positive associations with percent water in those aged 15-19 years.

After adjustment for other covariates, interactions of age and serum levels of testosterone (p=0.02) and progesterone (p=0.03) were associated with percent water, and estradiol with total water (p=0.07).

Conclusions

Serum levels of sex hormones were associated with breast tissue composition in young women aged less than 20, while GH and SHBG were associated with breast tissue composition in all young women.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A123.
Abstract A126: Characteristics of menstruation and pregnancy and the risk of lung cancer in women
Authors: Koushik Anita , Parent Marie-Elise , Siemiatycki Jack
Published: May 2012

A126

Differences between men and women in the descriptive epidemiology of lung cancer suggest that hormonal factors may influence lung carcinogenesis in women. Few epidemiological studies have been conducted on hormone-related variables and lung cancer risk and the findings have not been consistent. We investigated the association between characteristics of menstruation and pregnancy in relation to lung cancer risk in a population-based case-control study carried out in Montreal, Canada. Between January 1996 and December 1997, newly diagnosed lung cancer cases were identified and recruited from 18 Montreal-area hospitals that together diagnose 98% of cases that occur among Montreal residents. Population controls from Montreal were identified from the provincial electoral lists and were randomly selected, stratified to the expected age and sex distribution of cases. The participation rate was 81.7% among cases and 69.4% among controls. Among cases, interviews were conducted an average of 12.1 months after diagnosis. For each variable, odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression modeling. Each hormone-related variable was modeled separately. Associations were also examined according to age at diagnosis and level of smoking and by lung cancer histology. All statistical tests were two-sided. Among 422 women with lung cancer and 577 controls, we observed that most characteristics of menstruation and pregnancy were not associated with the risk of lung cancer. However, an increased lung cancer risk was observed for women who had had surgical menopause with bilateral oophorectomy compared to women who had had a natural menopause (OR=1.95, 95% CI: 1.29-3.17). These results did not vary by age at diagnosis or level of smoking, and they were similar for different histological types. Our results suggest that hormonal factors, related to surgical menopause and/or ovary removal, may play a role in the risk of lung cancer. Further studies are needed to confirm these findings, and to assess the possible contribution of hormone replacement therapy.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A126.
Abstract A129: Alpha-fetoprotein-derived peptide (AFPep): A novel drug in translational studies for the treatment and prevention of breast cancer.
Authors: Jacobson Herbert , Bennett James , Andersen Thomas
Published: May 2012

A129

It has been well established that parity is associated with reduced lifetime risk for breast cancer. Recent U.S. Census data note that the proportion of American women who remain nulliparous has doubled over the last 30 years. These data suggest that the incidence of breast cancer will increase in the coming years. Is there a molecule in pregnancy that can be isolated, shown to inhibit breast cancer, and be converted into a drug that can be used to treat and prevent breast cancer?

The studies reported here demonstrate that a-fetoprotein (AFP) is such a molecule, that the anti-breast cancer site within that molecule is an 8-amino acid sequence in the third domain of the protein, and that this site has been synthesized in a form that can be used as a novel, non-toxic drug for the treatment and chemoprevention of breast cancer. We refer to this agent as AFPep.

AFPep is active after oral administration. It stops the growth of human breast cancers growing as xenografts in immune deficient mice, and it prevents the development of carcinogen-induced mammary cancers in rats. Its anti-breast cancer activity is additive in combination with tamoxifen, and it prevents the uterine hyperplasia induced by tamoxifen. Moreover, AFPep is active against breast cancers which have become resistant to tamoxifen. Its anti-oncotic mechanism is different from that of tamoxifen, aromatase inhibitors, anti-gonadotropins, and cytotoxic chemotherapy. There has been no evidence of toxicity in mice and rats receiving AFPep even when its dose was escalated 100-fold above its effective dose. Grant proposals are currently in review to support further development of AFPep including completion of its preclinical toxicology and initiation of Phase I clinical trials.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A129.
Abstract A131: Molecular events associated with the anti-tumor effects of black raspberries in N-nitrosomethylbenzylamine-induced rat esophageal carcinogenesis
Authors: Wang Li-Shu , Dombkowski Alan , Larue Bethany , Cukovic Daniela , Mukundan Anju , Henry Cassandra , Rocha Claudio , Lechner John , Stoner Gary
Published: May 2012

A131

We reported that the feeding of a diet containing 5 or 10% freeze-dried black raspberries (BRB) to N-nitrosomethylbenzylamine (NMBA)-treated rats results in a 39-64% reduction in the number of esophageal papillomas when using either anti-initiation or anti-promotion/progression protocols. The molecular events associated with the effects of BRB on NMBA-induced preneoplastic and papillomatous esophageal lesions however, have not been fully elucidated. In the present study, 4-5 week-old male F344 rats were injected s.c. with NMBA (0.3 mg/kg b.w., 3x/wk for 5 wks) after which they were fed either control diet or diet containing 5% BRB until the end of the study (35 wks). Control rats were injected s.c. with a solution of DMSO/water (20:80), the vehicle for NMBA. Esophagi from vehicle control, NMBA- and NMBA + BRB-treated rats were collected at 35 weeks for histologic grading, and for microarray and Real-Time PCR analyses. Treatment with 5% BRB reduced the number of preneoplastic lesions (dysplasias) and the number and size of papillomas in the esophagus of NMBA-treated rats. When compared to esophagi from vehicle control rats, NMBA treatment alone led to the differential expression of 4,807 genes in preneoplastic esophagus and 17,846 genes in esophageal papillomas. Treatment with 5% BRB resulted in a modulation towards control levels of expression of 626 genes in preneoplastic esophagus and 627 genes in papillomas. In both preneoplastic esophagus and in papillomas, the berry-modulated genes were associated with regulation of cell proliferation, inflammation and receptor-mediated pathways. Twenty-five genes were commonly modulated (down- or up-regulated) by BRB in both preneoplastic lesions and in papillomas. Interestingly, several of these genes are associated with matrix metalloproteinases involved in tissue invasion and metastasis, cell-cell adhesion and with calcium signaling. This is the first report suggesting that berries might influence genes involved in tissue invasion and metastasis in the rat esophagus. (Supported by NCI grant No. CA103180)

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A131.
Abstract A133: Time-dependent gene expression changes in a human colon polyp cell line induced by a clinically relevant concentration of atorvastatin
Authors: Elmore Eugene , Jain Aarti , Steele Vernon , Redpath J. Leslie
Published: May 2012

A133

The identification of biomarkers for chemopreventive agent efficacy in cell cultures from relative target tissues is of great importance. We have utilized a cell line from a human precancerous colon polyp cell line, VACO-235, to evaluate the changes in gene expression following continuous exposure to a clinically relevant concentration of atorvastatin (0.3 nM). The changes were monitored relative to the time matched controls at 48 and 96 hours of continuous exposure. The total RNA was isolated from three replicate cultures for each time point and from four replicate cultures of the time matched controls. The RNA was analyzed using Affymetrix human genome U133 plus 2 arrays. The data were analyzed using Genespring GX (Agilent Technologies) software to determine agent induced changes and to determine significant changes (P< 0.05) that occurred at either 48 or 46 hours (2613 genes) or at both 48 and 96 hours (334 genes). The data were further analyzed using Ariadne Pathway Studio. A number of pathways showed responses that suggest possible changes in the regulation of proliferation and apoptosis. The tumor necrosis factor receptor superfamily, member 1a pathway also showed important changes. Caspase 3 was induced by 5.4 fold at 48 hours and 2.4 fold at 96 hours. Pak1(P21 activated kinease 1), caspase 8, caspase 2, and caspase 4 were also induced. The p38 MAP kinase pathway showed inhibition with MAP3K4 (MAP/ERK kinase kinase 4), which showed a 5 fold inhibition at 48 hours and 2 fold at 96 hours. Changes in the p38 MAP kinase pathway suggested inhibition of multiple kinase genes. As could be predicted, the most significantly modified pathway was LRP5 (low density lipoprotein receptor-related protein 5) which regulates low density lipoprotein. This finding suggests that atorvastatin was evaluated at a concentration that was similar to in vivo. Longer term exposure studies are currently underway to determine the effect of continuous atorvastatin exposure on the culture morphology and growth of VACO 235 cells. These data suggest that the use of a clinically-relevant concentration of atorvastatin can modify the expression of several key potential biomarkers for colon cancer prevention.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A133.
Abstract A136: A systems approach to the preclinical evaluation of targeted chemoprevention for lung cancer
Authors: Hazra Saswati , Krysan Kostyantyn , Walser Tonya , Gardner Brian , Lee Gina , Shay Jerry , Minna John , Horvath Steve , Dubinett Stven
Published: May 2012

A136

The possibility of an “individualized medicine” approach to chemoprevention targeted to the specific molecular abnormalities in the individual at risk has been suggested as a means to tailor prevention strategies (Markowitz, N Engl J Med. 2007;356:2195-8). In order to initiate targeted chemoprevention for lung cancer, we have developed a pre-clinical system to assess potential chemoprevention agents against mutated human bronchial epithelial cell lines (HBEC). HBECs are exposed to drugs such as rosiglitazone, erlotinib and celecoxib and selected proliferative responses, gene expression, micro-RNA profiles and protein panels are assessed. This data is then assessed by systems analysis to determine the optimal chemopreventive agents against specific mutations. These data will ultimately be utilized both for agent selectivity and agent specific biomarker identification. In preliminary studies, we evaluated rosiglitazone, erlotinib and celecoxib against three genetically altered HBEC cell lines harboring mutations relevant in the pathogenesis of human lung cancer (p53 knockdown, K-rasV12 and EGFR L858R mutations). As a model of long-term tobacco exposure, NNK- treated HBEC cells are also being utilized. In addition to selected proliferation assays, we assessed each agent against HBEC cell lines and evaluated a 50 protein luminex profile as well as a panel of more than 700 micro RNAs. These potential chemopreventive agents reveal specific patterns of alterations in proliferation, gene expression, protein secretion and microRNA profiles. Based on these findings, assessment of combinations of preventive agents are in progress. We anticipate that these methods will assist in the development of agent specific biomarkers and a personalized approach to chemoprevention for lung cancer.

This work is supported by the UCLA SPORE in Lung Cancer P50 90388, UT Southwestern SPORE in Lung Cancer P50CA75907 and The Flight Attendant Medical Research Institute (FAMRI) Young Clinical Scientist Awards.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A136.
Abstract A137: NO initiates progression of human melanoma via a feedback loop mediated by APE/Ref-1, new opportunities for chemoprevention.
Authors: Yang Zhen , Yang Sun , Misner Bobbye , Chiu Rita , Meyskens Frank
Published: May 2012

A137

It is well recognized that nitric oxide (NO) is involved in tumor progression, including melanoma. Measurement of proliferative and metastatic capacity by MTS and Matrigel-invasion assays respectively were done. NO-treated melanoma cells(especially metastatic Lu1205) exhibited a higher capacity compared with control, especially metastatic Lu 1205 cells. Apurinic/apyrimidinic endonuclease-1/redox effector factor-1 (APE/Ref-1) is a multifunctional protein, and its role in tumor biology has attracted considerable attention. To determine whether APE/Ref-1 plays a role in mediating NO-stimulation of melanoma progression, we investigated the effect of DETA/NO on levels of APE/Ref-1 and related downstream targets (Activator Protein-1 (AP-1)/Jun D, Matrix Metalloproteinase-1 (MMP-1), Bcl-2, and inducible nitric oxide synthase (iNOS)) by Western Blot and RT-PCR analysis. Following DETA/NO treatment, APE/Ref-1 and other downstream molecules were induced. Knockdown of APE/Ref-1 or AP-1/Jun D by specific siRNA markedly reversed the induction by NO stress of target proteins. These results present evidence for the existence of a functional feedback loop contributing to progression and metastatic capacity of melanoma cells. Resveratrol has been demonstrated to be an APE/Ref-1 inhibitor, and significant decreases in AP-1/JunD, MMP-1, Bcl-2, and iNOS protein levels occurred after exposure to resveratrol. This phenolic antioxidant as well as other inhibitors of Ref-1 may be an appropriate choice for combining with other compounds against melanoma cells that develop resistance by up-regulations of these molecules.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A137.
Abstract A138: Vaccination with HPV 16 L2E6E7 with GPI-0100 adjuvant elicits protective humoral as well as cell-mediated immune responses
Authors: Karanam Balasubramanyam , Roden Richard , Gambhira Ratish , Jagu Subhashini
Published: May 2012

A138

L1 virus-like particle (VLP) vaccines provide effective protection against Human papillomavirus (HPV) type from which the L1 was derived via the induction of neutralizing antibodies. While partial protection can occur against very closely related types, it is generally type-restricted and necessitates highly multivalent L1 VLP vaccines to obtain broad coverage. The minor capsid protein, L2, is emerging as an attractive alternative cross-protective antigen. Unfortunately, neither L1 VLP nor L2-based vaccines are effective against pre-existing disease, suggesting the need to develop therapeutic vaccines. Unlike the capsid proteins, the E6 and E7 oncoproteins are both required to maintain and expressed throughout cervical intraepithelial neoplasia (CIN) and cancer. TA-CIN, a vaccine comprising the HPV16 L2, E6 and E7 in a single tandem fusion protein, attempts to combine the advantages of broad cross-protection against HPV transmission with therapeutic responses targeting HPV16 early proteins. Here we test TA-CIN formulated along with GPI-0100, a semi-synthetic quillaja saponin analog, that was developed to promote both humoral and cellular immune responses. TA-CIN administered subcutaneously to mice three times at monthly intervals (125μg of clinical-grade protein) with 50μg GMP-grade GPI-0100 was found to elicit high titer antibodies that effectively neutralized not only HPV16 but also other oncogenic HPV types including HPV18, HPV31, HPV45, HPV58. Similarly, vaccination of pigtail macaques (Macaca nemestrina) with TA-CIN (three doses of 125μg of TA-CIN with 1000μg GMP-grade GPI-0100 at monthly intervals) was well tolerated and induced serum antibodies that neutralized HPV16, HPV18, and HPV31 in vitro. Notably, vaccination of mice with TA-CIN protected them from cutaneous HPV16 challenge as effectively as HPV16 L1 VLP. Combination of TA-CIN along with adjuvant GPI-0100 enhanced production of E7-specific, interferon gamma producing CD8+ T cell precursors by 20-fold. Vaccination with TA-CIN in adjuvant GPI-0100 completely prevented tumor growth after challenge with 5 x 104 HPV16-transformed TC-1 tumor cells. Protection of the mice immunized with TA-CIN plus GPI-0100 against TC-1 in a prophylactic setting was significantly more effective than TA-CIN alone or GPI-0100 alone. Patients vaccinated with TA-CIN alone develop weak HPV neutralizing antibody and E6/E7-specific T cell responses. GPI-0100 has been used safely as an adjuvant in several human trials suggesting that the combination of TA-CIN and GPI-0100 warrants further study.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A138.