bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B25: Information on perceived breast cancer risk may help tailor risk assessment among high risk women
Authors: Sprenger Amber , Gross Amy , Axilbund Jennifer , Helzlsouer Kathy , Armstrong Deborah , May Betty , Visvanathan Kala
Published: May 2012

B25

Information on perceived breast cancer risk may help tailor risk assessment among high risk women. />Background: Women with a family history of breast cancer (FHBC) are believed to overestimate their breast cancer risk more than women from the general population. However there is little research examining which factors predict variations in perceived and actual risk among women with FHBC. We examined whether specific lifestyle and demographic factors are associated with over- or under-estimating BC risk. Methods: Cross-sectional data on 767 women with FHBC who attended the Breast and Ovarian Surveillance Service clinic at Johns Hopkins between February 1996 and March 2008 and were cancer-free were identified from a prospective database. Prior to their appointment women completed a questionnaire measuring breast cancer risk perception (5-year and life-time) and demographic and lifestyle behaviors. Detailed information on family history was also provided. Actual risk was determined using the Tyrer-Cuzick model. Odds ratios (OR) and 95% confidence intervals (CI) of being an over-estimator or under-estimator (in comparison with accurate estimators) were estimated from age-adjusted logistic regression. Results: Risk estimates were provided by 69% (531) of women. Those who did not provide risk estimates had significantly more breast cancer-affected family members (p = 0.040) and were more likely to be African American (p=.016). The median actual risk level was 23.79% (range: 0.70%-96.33%). In comparison with women who were accurate in their BC risk estimates (n=92), women who underestimated their lifetime BC risks by more than 10 percentage points (n=37) were younger (OR=0.94, 95%CI 0.90-0.98). In comparison to accurate women, women who overestimated their lifetime BC risk by more than 30 percentage points (n = 295) had a higher body mass index (BMI) (OR=1.08, 95%CI 1.03-1.13), had fewer years of education (OR=0.86, 95%CI 0.75-0.99), had more family members affected with BC (OR=1.28, 95%CI 1.02-1.60), and were more likely to have ever smoked (OR=1.79, 95%CI 1.08-2.97). Conclusion: Distinct profiles were observed for women who underestimated, overestimated or were accurate in their risk perception suggesting they may benefit from more tailored approaches to risk assessment.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B25.
Abstract B78: The X protein of hepatitis B virus induces PI3K/Akt pathway to overcome gentoxic stress-related cyclin D1 degradation and growth arrest
Authors: Kumar Vijay , Mukherji Atish , Janbandhu Vaibhao
Published: May 2012

B78

Growth arrest represents an innate barrier to carcinogenesis. DNA damage and replicational stress are known to induce growth arrest and apoptotic death to avert genomic instability and consequently carcinogenesis. Working on the genotoxic stress induced by hydroxyurea and methylmethanesulfone, we observed a growth arrest at G1/S-phase that was mediated by destabilization of cyclin D1. The growth arrest was independent of the stability of cdc25A and preceded transcriptional up-regulation of p21waf1. Cyclin D1 destabilization involved its phosphorylation by GSK-3beta at threonine-286 since overexpression of the kinase-dead mutant of GSK-3beta or cyclin D1T286A mutant conferred stability to cyclin D1. Further, overexpression of cyclin D1T286A also helped in bypassing G1/S phase growth arrest. We also observed a rapid inactivation of Akt/PKB kinase in the presence of hydroxyurea. Enforced expression of the constitutively active Akt or viral oncoprotein HBx was sufficient to overcome growth arrest independent of ATR signaling and stabilized cyclin D1. Thus, the present work not only establishes cyclin D1 to be a novel mediator of genetoxic stress signaling but also explains how a deregulated mitogenic signaling or a viral oncoprotein can help bypass growth arrest.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B78.
Abstract B81: Human papillomavirus-16 (HPV-16) detected in squamous cell lung cancer.
Authors: Aguayo Francisco , Castillo Andres , Koriyama Chihaya , Eizuru Yoshito , Akiba Suminori
Published: May 2012

B81

Background

Human papillomavirus (HPV) is an epitheliotrophic double stranded DNA virus that has been found in lung cancer at variable frequencies around the world. The role of HPV in the etiology of this neoplasia and a specific association with histological type remain controversial. We previously reported HPV was associated with squamous cell lung carcinomas from Chile and HPV-16 was integrated into the host genome with low viral load.

Material and Methods

In order to study HPV presence and role in other countries, 60 lung carcinomas from Asia (China, Pakistan and Papua New Guinea) were analyzed using polymerase chain reaction (PCR). HPV-16 integration status and viral load was determined using real-time PCR and HPV-16 E6 protein expression was analyzed using immunohistochemistry. In order to determine the role of HPV-16 variants, L1 and E6 regions were sequenced in squamous lung carcinomas and cervical carcinomas from Chile.

Results

We detected high-risk HPV-16 in 8/60 (13%) specimens. According to histological type, HPV-16 was detected in 8/18 (44%) squamous cell carcinomas, 0/38 (0%) adenocarcinomas and in 0/4 (0%) small cell carcinomas and this difference was statistically significant (p<0.001). HPV-16 viral load was ranged between 411 to 2345 copies/100 ng of genomic DNA. We found that in 63% of positive samples, the HPV-16 genome was fully integrated into the host genome. HPV-16 E6 oncoprotein expression was detected in 1/8 (12.5%) HPV-16 positive cases. In addition, HPV-16 Asian-American (AA) variant with higher oncogenic potential was predominant in squamous cell carcinomas from Chile compared with European (E) variant that was predominant in cervical carcinomas.

Conclusion

Taken together, these findings suggest that HPV infection might be associated with a subset of squamous cell lung carcinomas and suggest a differential tropism of HPV-16 variants in bronchial and cervical epithelia. More studies about etiological role of HPV and the specific role of HPV-16 AA variant in squamous cell lung carcinomas development are warranted.

This work was financed by Grants-in-Aid for Scientific Research on Priority Areas (12218231 and 17015037) of the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B81.
Abstract B84: NADPH oxidase 1 (NOX1) and related NOX isoforms as key mediators of NFκB signaling in colon cancer
Authors: Wang Rong , Dashwood Wan-Mohaiza , Nian Hui , Tsuchiya Naoto , Nakagama Hitoshi , Dashwood Roderick
Published: May 2012

B84

NADPH oxidase/dual-oxidase (Nox/Duox) family members have been implicated in nuclear factor kappa-B (NFκB)-mediated inflammation and inflammation-associated pathologies. In rats given 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) alternating with a high-fat diet, Nox1, Nox4 and Duo2, but not Nox2, were over-expressed in colon tumors at 1 year, as shown by quantitative RT-PCR and immunoblotting. Over-expression of Nox/duox isoforms coincided with increased nuclear NFκB protein, and elevated levels of downstream targets IL-1β, IL6, TNF-α and TNFR1. Over-expression of Nox1 and activation of NFκB also occurred at early stages of colon carcinogenesis, prior to tumor development. Nox/Duox isoforms were over-expressed in primary human colon cancers and in several human colorectal cancer cell lines. In HT29 cells, silencing of Nox1 inhibited nuclear translocation and DNA binding activity of NFκB, attenuated downstream targets IL1β, c-myc, and cyclin D1, and blocked lipopolysaccharide-induced phosphorylation of IκB kinaseα/β, resulting in G1 arrest. We conclude that the Nox1-NFκB pathway is important in colon tumorigenesis, and that Nox1 may provide a target for novel therapeutic strategies against colon cancer development.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B84.
Abstract CN05-03: Modulating ER stress-induced autophagy to cancer control
Authors: Yin Xiao-Ming
Published: May 2012

CN05-03

Two major protein degradation systems are present in the cell, the ubiquitin proteasome system and the autophagy machinery. Inhibition of proteasome can activates autophagy, suggesting that the two systems are functionally coupled. Autophagy plays a compensatory role as suppression of autophagy promotes the accumulation of polyubiquitinated protein aggregates. Autophagy is likely activated in response to endoplasmic reticulum stress caused by misfolded proteins during proteasome inhibition. Indeed, direct disturbing ER environment with chemicals such as A23187, tunicamycin, thapsigargin and brefeldin A, can induce autophagy. Suppression of a major unfolded protein response pathway mediated by IRE1 by either gene deletion or RNAi dramatically suppresses the activation of autophagy by proteasome inhibitors or ER stress inducers. Interestingly, JNK but not XBP-1, both of which are the known downstream targets of IRE1, seems to participate in autophagy induction by proteasome inhibitors. Autophagy induced under these conditions is important for controlling endoplasmic reticulum stress and for reducing cell death in cancer cells. Thus a combined use of proteasome inhibitors and autophagy inhibitors enhances tumor cell death both in vitro and in vivo. Notably, this enhanced toxicity was not observed in non-transformed normal cells, suggesting that the impact of autophagy on cell survival during endoplasmic reticulum stress is likely contingent on the oncogenic status of cells. These findings indicate that blocking both autophagic and proteasomal degradation systems could be a novel and selective strategy for cancer control via the regulation of ER stress.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN05-03.
Abstract ED02-03: The integration of new in vivo and in vitro diagnostic technologies with new therapeutics to accelerate the development and approval of new cancer therapeutics
Authors: Heath James
Published: May 2012

ED02-03

The Nanosystems Biology Cancer Center (NSBCC) was founded three years ago by the NCI to accelerate the translation of systems biology models of cancer into clinical tool for cancer diagnosis and treatment. Over the past three years we have demonstrated that we can go, within a period of 1 to 1.5 years, from a concept on paper to Phase I trials or demonstrations in humans for three major cancer technologies: in vivo PET molecular imaging probes of cancer, siRNA-based cancer therapeutics, and highly multiplexed in vitro diagnostic assays. These advances represent major cost reductions and efficiency increases in three major aspects of cancer clinical care. However, the goal of achieving the same level of cost reductions and efficiency improvements in pushing a new therapeutic from a Phase I trial to an FDA-approved drug remains a daunting challenge. In this talk, I will discuss how the integration of in vivo and in vitro diagnostic tools with drug trials can be done to achieve this goal, and I will give examples of how we are beginning to push in this direction.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED02-03.
Abstract PR-14: Regression of rectal polyps in familial adenomatous polyposis patients with freeze-dried black raspberries
Authors: Stoner Gary , Hasson Henrietta , Sardo Christine , Wang Li-Shu , Pearl Dennis , Buchta Anthony , Burke Carol
Published: May 2012

PR-14

Familial adenomatous polyposis (FAP) is a dominantly inherited disease characterized by the early onset of colonic polyposis and a risk of colon cancer of nearly 100% by the age of 40. The traditional management of FAP is colectomy followed by lifelong endoscopic surveillance of the rectum and removal of rectal polyps. Our laboratory has reported on the ability of freeze-dried black raspberry (BRB) powder to prevent chemically-induced cancer in the rodent colon. Administration of BRB powder at 2.5, 5 and 10% in a synthetic diet to rats treated with the carcinogen, azoxymethane, reduced the development of colonic adenocarcinomas by 50 - 80%. BRBs prevent cancer in rodents by reducing cell proliferation, inflammation and angiogenesis, and by stimulating apoptosis and differentiation. We also showed in a Phase I clinical trial that BRB powder is well tolerated by humans when administered in a slurry of water at 45g/day for 7 days. Based upon these results, we undertook the present study to determine if BRB might regress rectal polyps in FAP patients. Fourteen FAP patients who had undergone a colectomy were treated with BRB daily for a period of nine months. Seven patients received BRB powder (20g/3x/day) orally in a slurry of water plus two suppositories (each composed of 700 mg BRB) that patients inserted into the rectum one hour before bedtime. The other seven patients were randomized to receive an oral placebo plus the two rectal suppositories. Rectal polyp counts were taken at time zero and after nine months of BRB treatment. The number of rectal polyps was reduced by a median of 43% at nine months overall including a median reduction of 59% in patients treated by both routes and 36% in patients treated with the suppositories only. Polyps and aberrant crypt foci were collected both before and after berry treatment, and molecular studies are underway to determine the mechanism(s) for BRB-induced rectal polyp regression in FAP patients.

(Supported by NCI grant CA103180 and USDA grant 38903-03560).

Citation Information: Cancer Prev Res 2008;1(7 Suppl):PR-14.
Abstract A102: Genetic reduction of circulating IGF-1 decreases growth of pancreatic tumors in an orthotopic transplant model
Authors: Lashinger Laura M. , Malone Lauren , Perkins Susan N. , Colby Jennifer K.L. , Fischer Sue M. , Hursting Stephen D.
Published: May 2012

Pancreatic cancer is the 4th deadliest cancer in the U.S. Obesity has emerged as a significant and modifiable risk factor for pancreatic cancer. Calorie restriction (CR) is an anti-obesity intervention that has been shown in many model systems to have potent anticancer effects. Levels of bioavailable insulin-like growth factor (IGF)-1, an established mitogen in a variety of cancer cell lines, increase in response to positive energy balance and decrease with CR. We hypothesized that the genetic reduction of circulating IGF-1 levels seen in liver-specific IGF-1-deficient (LID) mice would diminish the tumor burden of orthotopically transplanted pancreatic cancer cells, similar to CR, while administration of exogenous IGF-1 would restore the tumor burden. To test this hypothesis, mouse pancreatic cancer cells (JC101, derived from our BK5-COX-2 transgenic mouse model of spontaneous pancreatic cancer) were orthotopically transplanted in LID and littermate control (LC) mice. LID mice were also randomized to receive Alzet miniature osmotic pumps (implanted subcutaneously) continuously infusing either vehicle (n=8) or 1 µg/hr of recombinant human IGF-1 (Increlex®, Tercica, Inc., Brisbane, CA; n=8). LC mice were infused with vehicle (n=8). Mice were killed 28 days after injection, blood was collected by cardiac puncture and serum samples were stored at −80°C, and tumors were weighed and fixed in 10% normal buffered formalin for histological and immunohistochemical (IHC) analysis. IHC staining was performed on paraffin-embedded tissues using antibodies against Ki67 and cyclin D1 to assess proliferation. LID mice exhibited significantly smaller tumors (0.20 ± 0.02 g) than LC mice (0.45 ± 0.11 g, p<0.05) or LID + IGF-1 mice (0.57 ± 0.14 g, p<0.01). Serum IGF-1 levels were reduced approximately 60% in the LID mice relative to the LC mice (p<0.01), while infusion of human IGF-1 resulted in total serum IGF-1 levels (murine plus human IGF-1) exceeding either LC or LID mice (p<0.01). In contrast, insulin and leptin levels in LID mice were significantly higher than those seen in LC (p<0.05) or LID+IGF-1 (p<0.01) mice. Consistent with tumor burden data, LID tumors, relative to LC and LID + IGF-1, displayed less expression of proliferative markers. These findings suggest that genetic reduction of circulating IGF-1 levels decreases transplanted pancreatic tumor growth despite increased levels of insulin and leptin, underscoring the importance of the IGF-1 pathway as a pancreatic cancer prevention target.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A102.
Abstract A112: Flavonol intake may modify the association between interleukin genetic polymorphisms and colorectal adenoma recurrence in the polyp prevention trial
Authors: Bobe Gerd , Murphy Gwen , Albert Paul S. , Sansbury Leah B. , Lanza Elaine , Schatzkin Arthur , Colburn Nancy H. , Cross Amanda J.
Published: May 2012

Background: Interleukin (IL) 1β, 6, and 8 are pro-inflammatory cytokines that may promote colorectal carcinogenesis, whereas IL-10 is an anti#x2010;inflammatory cytokine with pro- and anti-carcinogenic effects. Single nucleotide polymorphisms (SNPs) in the promoter regions of these cytokine genes may alter inflammation and consequently colorectal carcinogenesis. Flavonols, found in fruits and vegetables, have anti-inflammatory and chemopreventive properties and they may modify the effect of SNPs in IL-encoding genes on colorectal carcinogenesis.

Aims: To determine whether SNPs in IL-1β, 6, 8, and 10 were associated with their corresponding serum concentrations and adenoma recurrence and whether flavonol consumption modified these associations.

Methods: Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for SNPs in IL-encoding genes, flavonol intake, and risk of adenoma recurrence in 1,687 participants of the Polyp Prevention Trial, a 4-year trial of a low-fat, high-fiber, high-fruit & -vegetable, flavonol-rich diet.

Results: Overall, SNPs in genes encoding IL-1s, IL-6, IL-8, IL-10 were not associated with their corresponding serum concentrations or adenoma recurrence. However, statistically significant interactions were observed between flavonol intake and IL-8 -251 T > A genotype for any (P = 0.04) and advanced adenoma recurrence (P = 0.01). Individuals consuming above the median level of flavonol intake and had IL-8 -251 AA (vs. TT) had an increased risk of any (OR = 1.54, 95% CI: 1.00–2.39) and advanced adenoma recurrence (OR = 4.44, 95% CI: 1.32–15.0).

Conclusion: Our results suggest that flavonol consumption may modify the association between IL-8 SNPs and colorectal adenoma recurrence.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A112.
Abstract A116: Carotenoid intakes and risk of breast cancer by estrogen receptor status: A pooled analysis of 16 prospective cohort studies
Authors: Zhang Xuehong , Smith-Warner Stephanie A.
Published: May 2012

Associations between dietary carotenoid intakes and breast cancer risk by estrogen receptor (ER) status remain unclear. We prospectively investigated these associations using a pooled analysis of the primary data from 16 cohort studies. During follow-up of 996,735 women ranging from 6 to 22 years, 34,524 breast cancer cases (4,552 ER-/19,722 ER+) were identified. We used Cox proportional hazards models to estimate study-specific relative risks (RRs) and 95% confidence intervals (CIs) and pooled the estimates using a random-effects model. In the preliminary analyses, comparing the highest and lowest quintiles of intake, beta-carotene intake was associated with a 10% lower risk of ER- breast cancer (pooled multivariate RR = 0.89 (95% CI: 0.81–0.99), Ptrend = 0.07) but not with risk of ER+ breast cancer (pooled multivariate RR = 1.02 (95% CI: 0.97–1.08), Ptrend = 0.76, Ptest for common effects by ER status = 0.02). Similarly, lutein/zeaxanthin intake was associated with a 13% reduced risk of ER- breast cancer (pooled multivariate RR = 0.87 (95%CI: 0.79–0.96), P trend = 0.04) but not with risk of ER+ breast cancer (pooled multivariate RR = 0.99 (95%CI: 0.93–1.06), Ptrend = 0.33, Ptest for common effects by ER status = 0.03). Alpha-carotene, beta-cryptoxanthin and lycopene intakes were not associated with breast cancer risk regardless of ER status. We observed similar associations when we categorized carotenoid consumption using identical absolute intake cutpoints or modeled intakes as continuous variables. The associations between carotenoid intake and risk of ER- and ER+ breast cancer did not differ by alcohol consumption, smoking habits, or menopausal status (Ptest for interaction > 0.05). Beta-carotene and lutein/zeaxanthin intakes appeared to be associated with a lower risk of ER-breast cancer but not with risk of ER+ breast cancer.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A116.
Abstract A120: Physical activity, body mass index, and vitamin D metabolite concentrations
Authors: Cisneroz Martin , Martinez Maria Elena , Thompson Patricia A. , Jacobs Elizabeth T.
Published: May 2012

Serum 25(OH)D concentrations have been demonstrated to be inversely related to several cancers. Because vitamin D can be obtained from both dietary sources and endogenous synthesis, the best strategy for improving vitamin D status is unclear, though abbreviated sun exposure, supplementation, and fortification have been suggested. Both physical activity and body mass index (BMI) have been shown to be correlated with 25(OH)D concentrations and themselves have been linked to colorectal neoplasia. We sought to investigate the types of physical activity that contribute most to circulating concentrations of vitamin D metabolites in a study population in southern Arizona, and to further evaluate the relative contributions BMI and type of physical activity to 25(OH)D concentrations. Individuals in the highest category of recreational physical activity were significantly more likely to have 25(OH)D concentrations of >=30 ng/ml as compared to those who were less active (p=0.007). After adjustment for BMI, age, race, sex, and season of blood draw, recreational physical activity remained statistically significantly associated with serum concentrations of 25(OH)D (p= 0.002), while household and sedentary physical activity were not related in either crude or adjusted models. For those participants with a normal BMI (18 < BMI <25), recreational physical activity had no influence on circulating concentrations of 25(OH)D (p=0.28); however, for those who were overweight (25<BMI<30) or obese (BMI >=30), recreational physical activity was directly associated with 25(OH)D levels (p=0.002 and p=0.009, respectively). For example, among obese participants, those in the lowest tertile of physical activity had a mean (+sd) 25(OH)D concentration of 22.4 + 7.8, while those in the highest tertile had levels of 27.0 + 7.2 (p-trend=0.009), possibly due to increased sun exposure. These results suggest that overweight individuals may be able to improve vitamin D status via recreational physical activity, which may in turn reduce the risk of several cancers.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A120.
Abstract A121: Genetic variation in CYP7A1, bile acids, and risk of adenoma in the proximal colon
Authors: Wertheim Betsy C. , Martinez Maria Elena , Alberts David S. , Jacobs Elizabeth T. , Lance Peter , Thompson Patricia A.
Published: May 2012

Background: Secondary bile acids, specifically deoxycholic acid (DCA), are probable carcinogens of colorectal cancer, particularly for lesions arising in the proximal colon. Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme in the conversion of cholesterol to primary bile acids in the liver. Genetic variation in CYP7A1 has been reported to modify risk of colorectal neopolasia arising in the proximal colon.

Methods: Using the placebo arm of our ursodeoxycholic acid chemoprevention trial, we studied the relationships between baseline fecal bile acid concentrations, six allelic variants in CYP7A1, and risk of proximal adenomas after three years of follow-up (n = 253). Because bile acid levels are strongly influenced by sex, we considered gender as a potential effect modifier. After testing four possible modes of inheritance for associations between genetic polymorphisms and proximal adenoma, we present results generated under log-additive models.

Results: The relationship between fecal DCA levels and development of proximal adenoma was strongly modified by gender (pinteraction < 0.001). Compared with the lowest quintile, higher levels of DCA were associated with significantly increased odds of proximal adenoma in men (OR = 7.14; 95% CI = 2.07 to 24.6) but non-significantly decreased odds in women (OR = 0.39, 95% CI = 0.13 to 1.20). These associations were slightly attenuated for men (OR = 5.82; 95% CI = 1.65 to 20.5) and women (OR = 0.44, 95% CI = 0.14 to 0.43) after adjusting for age and body mass index. In addition, analyses of two linked CYP7A1 SNPs (D′ = 0.75 and r2 = 0.5) showed that carriage of the minor allele for rs8192871 and rs13251096 lowered the odds of proximal adenoma by 45% (OR = 0.55; 95% CI = 0.36 to 0.85) and 41% (OR = 0.59, 95% CI = 0.40 to 0.89), respectively. Furthermore, these two SNPs were associated with DCA, such that carriers of two minor alleles had significantly lower fecal DCA levels (Kruskal-Wallis p = 0.003 for both SNPs). None of the other four CYP7A1 SNPs showed any association with proximal adenoma or fecal bile acid levels.

Conclusions: In this study population, CYP7A1 polymorphisms are significantly associated with risk of adenoma in the proximal colon, likely through their effects on bile acid levels. Sex, age, body mass index, and other factors that influence bile acid levels may further affect this risk.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A121.
Abstract A125: Genetic variation in nicotinic acetylcholine receptor region on chromosome 15q25 and lung cancer risk
Authors: Wei Chongjuan , Frazier Marsha , Wun Issac , Amos Chris
Published: May 2012

Lung cancer is the leading cause of cancer death in the U.S and is approximately 30% higher in African-Americans than in Caucasians. Recently, several groups including ours, using genome-wide association study, identified and replicated a region of chromosome 15q24–25.1 that had a highly reliable and significant association with lung cancer risk. Analysis of SNPs in this region identified association with variability in expression of exons 3–5 of CHRNA5. To identify additional variation that may be associated with lung cancer risk we started to re-sequence all of the exons and surrounding intron/exon boundaries for the genes in the region including CHRNA3, CHRNA5, PSMA4 and LOC123688, in 46 lung cancer cases and 46 control. Among these 4 genes, the first two are nicotinic acetylcholine receptor. Results of sequencing identified many new variants, and there were significantly more rare variants in cases than controls for CHRNA5. We evaluated 6 of these rare variants, located within the region of exon3–5 of CHRNA5 that were identified by resequencing, in a case controls study of African America population. However none of these 6 novel variants we identified were significantly more common in 467 cases than in 388 controls. In addition to these rare variants, we identified insertion/deletion variations in the promoters region of CHRNA5 and we will evaluate the association of these insertion/deletion variations with lung cancer in a large sample size of African America population. Taken together, the finding provides additional information on the association of nicotinic acetylcholine receptor region on chromosome 15q25 and lung cancer risk.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A125.
Abstract A128: Racial and ethnic disparities in lung cancer incidence, United States 1998–2005
Authors: Underwood Jon M. , Fairley Temeika , Townsend Julie , Tai Eric , Stewart Sherri
Published: May 2012

Background: Lung cancer is the second most commonly diagnosed cancer in men and women and the leading cause of cancer related death in the United States. Racial disparities in lung cancer incidence, treatment, mortality and survival have been documented. Advances in cancer surveillance, such as expansions in geographic coverage, allow for a more complete description of lung cancer incidence. This population-based study examines racial and ethnic disparities in incidence of lung cancer for the United States by demographic, geographic, and tumor characteristics.

Methods: We analyzed lung cancer incidence data obtained from cancer registries affiliated with Center for Disease Control's National Program of Cancer Registries and the National Cancer Institute's Surveillance, Epidemiology, and End Results program. The combined data collected on new cases diagnosed during 1998–2005 cover approximately 81% of the U.S. population. We calculated age-adjusted (2000 US standard) incidence rates, rate ratios, and 95% confidence intervals by demographic and tumor characteristics such as age, sex, race, ethnicity, U.S. Census Region, tumor grade, stage and histology.

Results: A total of 1,296,933 lung and bronchial cancer cases were diagnosed in the U.S. from 1998 until 2005. The overall incidence rate was (69.2/100,000 persons). Rates were higher among men (88.5) than women (55.1). Among men, incidence rates were highest for blacks (111.1) followed by whites (87.7), Asian/Pacific Islanders (API) (53.4) and American Indians/Alaska Natives (AI/AN) (53.3). Among women, whites (56.3) had the highest incidence rates followed by blacks (53.1), API (37.4), and AI/AN (27.3). Compared to non-Hispanics (71.8), Hispanics (37.5) had lower lung cancer incidence rates. More blacks were diagnosed at younger ages (40–59 years) compared to all other groups. At time of diagnosis, blacks have a higher percentage of distant disease (17%), and a higher percentage of poorly differentiated tumors (14%) compared to whites. Incidence rates differed amongst U.S. Census regions by race. Among whites, the highest lung cancer incidence rate was in the South (76.8) whereas rates among blacks (88.6), American Indians/Alaska Natives (61.5) & Hispanics (41.1) were highest in the Midwest.

Conclusion: This report updates previous findings from population-based studies describing U.S. disparities in lung cancer incidence. Differences in stage at diagnosis by race were also noted. We describe regional differences in incidence rates for certain racial and ethnic groups. These differences may reflect differences in tobacco use behaviors, early detection, treatment, or other unknown factors. Further investigation into the source of differences is warranted.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A128.
Abstract A130: Spatial and temporal patterns in female breast carcinoma incidence in Pennsylvania, 1985–2004
Authors: Han Yueh-Ying , Talbott Evelyn , Donovan Maryann
Published: May 2012

Objective: The assessment of spatial and temporal trends in breast carcinoma incidence can signal changes in ascertainment, changes in risk, and possibly point to changes in underlying risk factors. It is important to develop geographic maps to identify hot spots where cancer rates, by race and by histologic type, are elevated to better appreciate changes in cancer risk.

Methods: Incidence data for breast carcinoma, 1985–2004, was requested from the Pennsylvania Cancer Registry (PCR). Joinpoint regression model was applied to characterize age-, race- and histologic type-specific breast tumor incidence time trends in Pennsylvania (PA). Geographic Information System methods and spatial analysis is also being applied to these data to detect spatial clusters of diagnosed breast carcinoma in PA.

Results: Among whites, age-adjusted incidence for ductal carcinoma in situ (DCIS) increased significantly from 1985 to 1999 and incidence for lobular carcinoma in situ (LCIS) slightly increased from 1994 to 2004, although this increase was not significant. Among blacks, age-adjusted incidence for DCIS and LCIS increased significantly over the entire study period. Age-adjusted incidence for malignant breast carcinoma slightly decreased from 1997–2004 among blacks but more recently since 2001 has shown a sharp decrease among whites (annual percent change = −3.0). Between 1985 to 2004, for women under age of 40, age-adjusted incidence of breast carcinoma in situ (DCIS, LCIS, mixed) significantly increased 4.5% and 10.0% annually for whites and blacks, respectively. Incidence for malignant breast carcinoma slightly decreased over the study period.

To better define invasive breast cancer risk in PA, spatial clustering analysis performed to identify county-specific changes in malignant breast carcinoma incidence. This analysis showed significant spatial clustering in Pennsylvania (P=0.024) and the region of increased invasive breast cancer was clustered in seven southeastern counties.

Conclusion: Incidence for breast carcinoma in situ increased significantly among women in PA. An increase in invasive breast cancer was identified in seven southeastern counties. Factors responsible for the state-wide increase in breast carcinoma in situ and the elevated invasive breast cancer incidence in southeastern Pennsylvania should be carefully assessed.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A130.
Abstract A131: Antacid use and risk of larynx cancer in the NIH-AARP Diet and Health Study
Authors: Abnet Christian C. , Freedman Neal D. , Hollenbeck Albert , Schatzkin Arthur
Published: May 2012

Antacids are used to treat heartburn and their use serves as a proxy indicator of gastroesophageal reflux disease. We tested the association between self-reported antacid use and risk of laryngeal squamous cell carcinoma (N=240) in a prospective cohort study using Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) adjusted for potential confounders. We also estimate the risks for esophageal squamous cell carcinoma, and esophageal and gastric cardia adenocarcinomas for comparison. Antacid use showed significant associations with risk of esophageal and gastric cardia adenocarcinomas, 2.34 (1.79–3.06) and 1.45 (1.06–1.98) respectively, but not esophageal squamous cell carcinoma 0.99 (0.65–1.49). For laryngeal squamous cell carcinoma we found significantly increased risk 1.32 (1.01–1.72). In sex and smoking-status stratified models for the larynx, we saw a stronger association in men that had never smoked tobacco, 13.52 (2.89–63.22), compared to ever smokers, 1.20 (0.89–1.63). The small number of women with larynx cancer precluded stratified models. Our study suggests that gastroesophageal reflux may increase the risk of laryngeal squamous cell carcinoma.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A131.
Abstract A132: A descriptive study on the factors affecting mortality and disease-free survival among triple-negative breast cancer patients
Authors: Ong Kian Koc Jean Bernadette U. , Desai Ajit , Pomerantz Sherry , Kathy Pincus
Published: May 2012

Introduction: Triple-negative breast cancer patients have a worse prognosis as compared to other subtypes of breast cancer. Patients are usually diagnosed at a younger age. Tumor size is usually larger with poorly differentiated histology and possible visceral metastasis. Several studies have been published on the risk factors for developing triple negative breast cancer. On the other hand, factors predicting mortality after diagnosis among triple negative breast cancer patients is still lacking.

Objectives: The study aimed to describe the population of triple negative breast cancer patients diagnosed at Albert Einstein Medical Center from 2003–2007. Demographic data, risk factors and treatment interventions in this population were gathered. The measured outcomes were mortality and disease free survival.

Methods: This study was a retrospective review of women diagnosed with triple negative breast cancer at the Albert Einstein Healthcare Network Cancer Center in 2003–2007. Patients diagnosed with cancer metastasized to the breast and causes of death other than from complications of cancer were excluded from the study.

Statistical Analysis: Descriptive statistics and frequency distribution were used to categorize the characteristics of the subjects. Chi-square test was used for bivariate analysis. Logistic regression was used for multivariate analysis.

Results: A total of 214 patients were diagnosed with triple negative breast cancer from 2003–2007. 114 (53%) were African Americans, 84 (39%) were Caucasians and 16 (7%) belonged to other racial groups. The mean age of diagnosis was 56.6 (SD 15.9) years old. At the end of the four year period, 48 (22.4%) of the 214 patients died. Using chi square test and logistic regression, patients who underwent chemotherapy were less likely to die (95% CI 0.14 – 0.83, p 0.02, OR 0.35). The patients with tumor size more than 2 cm or had history of ischemic heart disease had increased mortality (95% CI 1.36 – 8.04, p 0.01, OR 3.3 and 95% CI 1.29 – 49, p 0.03, respectively). Chemotherapy was significantly associated with disease free survival (95% CI 1.49 – 18.65, p 0.01, OR 5.27). There was no significant association between mortality or disease free survival to age and race.

Conclusion: Early diagnosis and screening significantly affects treatment and survival outcome. Prompt chemotherapy may contribute to a patient's survival and disease free status. Tumor size more than 2 cms and the presence of ischemic heart disease were significant predictors of mortality outcome whereas age and race were not found to be associated with mortality or disease free survival.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A132.
Abstract A139: Effects of simvastatin and of a cyclic nonapeptide derived from alpha fetoprotein on the proliferation of ERα-positive mammary tumor cells in culture
Authors: Torres Cristian G. , Sierralta Walter Daniel
Published: May 2012

Introduction: Estradiol (E2) stimulate the progression of many mammary tumors, including those of dogs, by association to estrogen receptors (ER). We have recently reported on the effects of E2 and of an AFP-derived cyclized peptide (cP) on the proliferation of cancer cells from different mammalian species demonstrating that, in ER-positive cells, estradiol increased cell proliferation and the phosphorylation of ERK 1/2; these effects were effectively inhibited by the presence of cP in the culture medium. It has been reported that statins restrain the proliferation in culture of mammary tumor cells. We report here on the effects of statins and cP on the estrogen-stimulated proliferation of mammary tumor cells.

Aims: Evaluate the proliferation on mammary tumor cells after exposure to E2, without / with cP and simvastatin; comparison with the effect of ICI 182,780 (ICI).

Methods: MCF7 cells grown in DMEM F12 containing ITS (insulin, transferrin, selenium), 1% charcoal/dextran-twice-treated calf serum, 3% hydroxyethilated starch (HAES) and antibiotics were incubated of estradiol in the absence and presence of cP and various concentrations of simvastatin. Cell proliferation measurement and the assessment of viability (trypan blue) was done by haemocytometry.

Results and Conclusions: The proliferation of control (unstimulated) MCF7 cells, was not affected by the presence of either simvastatin or cP in the culture medium. The addition of 2nM E2 significantly increased the proliferation rate of the cells. The effect was reduced by cP to basal values, i.e. to the same extent than the specific antagonist ICI does. At the concentrations used, simvastatin had no effect on the proliferation of MCF7 cells stimulated with estradiol. We suggest that the effects of cP on the proliferation of estradiol-stimulated MCF7 cells are probably not related with a prenylation of ER.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A139.
Abstract A140: Chemoprevention of familial adenomatous polyposis by a flexible-heteroarotinoid (Flex-Het), SHetA2, in APCMin mice
Authors: Guruswamy Suresh , Benbrook Doris , Zhang Yuting , Qian Li , Mohammed Altaf , Rao Chinthalapally V.
Published: May 2012

Colorectal cancer is the second most common cancer in the western world with 1 million new cases worldwide each year. Flexible Heteroarotinoids (Flex-Hets) are a promising new class of anticancer compounds that regulate cell cycle progression, differentiation and apoptosis, as well as xenograft tumor growth and angiogenesis in many cancer types. The lead Flex-Het, Sulfur heteroarotinoid A2 (SHetA2), prevents DMBA-induced transformation in endometrial organotypic cultures in vitro and is currently in preclinical testing in the NCI RAPID program. In this study, the potential in vivo chemopreventive effects of SHetA2 were evaluated in APCmin/+ mice. Six-week old APCmin/+ mice were assigned to three different treatment groups with normalized distributions of males and females. Drug was dissolved in corn oil (0 - placebo, 30 mg/kg SHetA2, 60 mg/kg SHetA2) and administered by gavage five days per week for 12 weeks. There was no statistically significant difference in body weight between any of the treatment groups and controls. All mice were killed and the total number and size of tumors along the entire length of the intestine and colon were visually counted using a magnified lens. SHetA2-treated groups exhibited dramatic reductions in the total number of intestinal tumors at both doses (SHetA2 30 mg/kg - 60%, SHetA2 60 mg/kg - 54%, P<0.0001). On average, mice developed about 50 tumors per animal in the small intestine of the control, whereas there were only 20 tumors (SHetA2 30 mg/kg) and 23 tumors (SHetA2 60 mg/kg) in the treatment groups. Neither of the SHetA2 doses administered caused intestinal ulceration or acute toxicity. Both doses reduced the numbers of large (>2 mm), medium (1–2 mm) and small (<1 mm) adenomas. When data were analyzed for colon alone, the mean number of tumors per mouse was 2 in the control group, 0.3 with 30 mg/kg SHetA2, and 0.75 with 60 mg/kg SHetA2. Colon tumor incidences were 70%, 30% and 40% for control, 30 mg/kg SHetA2 and 60 mg/kg SHetA2, respectively. Although SHetA2 at both 30 mg/kg and 60 mg/kg appeared to cause a parallel trend in inhibiting tumor growth, 60 mg/kg concentration did not show greater inhibition than 30 mg/kg. Results from this study, for the first time, indicate that the Flex-Het, SHetA2, significantly decreases small intestinal and colon tumor formation. Currently, work is in progress to study the molecular and cellular activities involved in SHetA2 chemoprevention activity. (Supported by Kerley-cade chair endowment, R01-102947 and R01-CA-106713)

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A140.
Abstract A147: Curcumin modulates gene expression profile and delays tumor progression of prostate cancer
Authors: Killian Peter H. , Kronski Emanuel , Mirisola Valentina , Pfeffer Ulrich , Nerlich Andreas G. , Bachmeier Beatrice E.
Published: May 2012

Curcumin is a polyphenol, derived from the plant Curcuma longa that has promising anticancer properties in breast, colon, pancreas and some other cancer types. We recently demonstrated that the metastatic potential of breast cancer cells is strongly reduced upon treatment with Curcumin in a murine model of hematogenous metastasis: 68% of the mice treated had no or few metastases as opposed to 17% of the untreated mice.

In order to elucidate its anti-tumoral effects in prostate cancer, we used three human prostate cancer cell lines of clear defined and graduated tumorigenicity (LnCaPPC3) for our studies. In a first approach, we intended to obtain a complete picture of Curcumin-responsive genes and therefore we performed gene expression profiling (GeneChip Arrays Affymetrix) of Curcumin-treated cells versus non-treated cells followed by statistical analysis. Thereby we found 71 genes whose expression was significantly altered among which 8 genes were down-regulated. Treatment of prostate cancer cells with Curcumin reduced tumor cell proliferation (BrdU assay) and invasion (Matrigel assay) in a time and dose dependent manner. Furthermore expression of matrix-degrading enzymes (MMPs) which is a prerequisite for matrix degradation was significantly down-regulated on transcript as well as on protein level.

The underlying regulation mechanism involves the survival associated NFγB signaling pathway: Fluorescent translocation assays clearly demonstrated that Curcumin inhibits p65 translocation into the nucleus of the tumor cells, which in consequence leads to diminished transcription and expression of tumor progression related genes and gene products resulting in the induction of apoptosis.

Taken together, these features make Curcumin a promising drug for cancer chemoprevention and antitumor therapy of prostate cancer.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A147.
Abstract A26: CEA and CA 19-9 as biomarkers for prevention of gall bladder cancer
Authors: Kapoor Vinay K. , Agrawal Vinita , Goel Amit , Krishnani Narendra , Pandey Rakesh , Agrawal Suraksha
Published: May 2012

Objective: Gall bladder cancer (GBC) is the commonest biliary tract cancer worldwide. It is the commonest gastro-intestinal cancer in women in northern India; it is common in Native American Indian people also. GBC is usually associated with gall stones (GS) and chronic cholecystitis (CC); xantho-granulomatous cholecystitis (XGC) is a variant of CC. Most patients with GBC are diagnosed at an advanced stage and overall prognosis is poor. Prophylactic cholecystectomy in patients with asymptomatic GS can prevent GBC, but it can not be advised in everyone with GS. There is a need to identify some bio-markers for early diagnosis and prevention GBC.

Materials and Methods: We evaluated the immuno-histo-chemical (IHC) expression of carcino-embryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 in histo-pathologically confirmed GBC (n=51), CC (n=68), XGC (n=42) and normal GBs removed during operations on bile duct, liver and pancreas (n=10). IHC was performed using mouse monoclonal primary antibodies for CEA (Clone II-7, 1:100, Dako) and CA 19.9 (Clone 116-NS-19-9, 1:100, Dako) using labeled Streptavidin Biotin Peroxidase method. Intensity of staining was recorded as absent (0), mild (1), moderate (2) and intense (3) while the percentage of nuclei stained were scored as absent/<5% (0), >5 <10% (1), 10–50% (2) and >50% (3). The total score was calculated by adding the intensity score and the percentage score and ranged from 0–6. A score of ≥3 was considered as positive.

Results: CEA expression was present in 42/51 (82%) of GBC - it was apical in 13, focal cytoplasmic in 15 and diffuse cytoplasmic in 14 cases. CEA expression was seen in 18/68 (27%) of CC - it was apical in all 18 with focal cytoplasmic in 9. CEA expression was seen in 4/42 (10%) of XGC - it was apical in all 4; many cases with XGC, however, did not have epithelium. All 10 normal GBs showed apical CEA expression. Diffuse cytoplasmic staining of CEA was seen in only GBC and was not seen in CC, XGC and normal GBs. CA 19-9 expression was seen in 38/51 (75%) of GBC - all cytoplasmic; all 13 CA19-9 negative GBCs were high grade on histopathology. All CC, XGC and normal GBs showed apical and diffuse cytoplasmic positivity for CA 19-9.

Conclusion: Tumor markers such as CEA and CA 19-9 can be used to screen patients with asymptomatic GS to identify a sub-group with higher risk to develop GBC who can then be offered prophylactic cholecystectomy for secondary prevention of GBC.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A26.