bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 856: Correlation of prognosis and histologic patterns by the IASLC/ATS/ERS classification in invasive pulmonary adenocarcinoma: A meta-analysis
Authors: Park Keon Uk , Kim Jin Young , Ryoo Hun Mo , Hwang Ilseon
Published: August 2015

Background: Invasive pulmonary adenocarcinoma is composed of five histologic patterns including lepidic, papillary, acinar, solid, and micropapillary patterns by the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society classification. Many researches for histologic pattern and survival rates were performed, but confirmative relationships of histologic pattern and patient's prognosis are unclear. Methods: We searched PubMed using the keywords “IASLC/ATS/ERS classification” and “International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society”. Review articles and case reports were excluded, and duplicated data, insufficient data, and overlapping articles are also excluded. The pooled analysis was performed with the Comprehensive Meta-analysis Software version 2.0. Results: Lepidic predominant pattern had significantly lower recurrence and expire than acinar, papillary, solid or micropapillary pattern. Acinar or papillary pattern had significantly lower recurrence and expire than solid or micropapillary pattern. Conclusions: Invasive adenocarcinoma with lepidic predominant pattern has better prognosis than that with the other predominant patterns. Acinar and papillary predominant patterns have better prognosis than solid and micropapillary predominant patterns in invasive pulmonary adenocarcinoma. There are no different prognoses between acinar and papillary predominant patterns, and solid and micropapillary predominant patterns of invasive pulmonary adenocarcinoma.

Citation Format: Keon Uk Park, Jin Young Kim, Hun Mo Ryoo, Ilseon Hwang. Correlation of prognosis and histologic patterns by the IASLC/ATS/ERS classification in invasive pulmonary adenocarcinoma: A meta-analysis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 856. doi:10.1158/1538-7445.AM2015-856
Abstract 860: Effects of breastfeeding and oral contraception use on the risk of breast cancer recurrence: A multinational study
Authors: Lehman Teresa A. , Shaik Mohammed , Modali Ramakrishna V. , Hrinczenko Borys
Published: August 2015

Introduction:

Breastfeeding (BF) decreases and oral contraceptive (OCP) increases the incidence of breast cancer (BC). However, their role in the recurrence of breast cancer (rBC) has not been established. The aim of our study was to examine the association of maternal factors in the rBC.

Methods:

Data were obtained from the Global Epidemiological Study (GES), an IRB approved multinational biorepository and database to assess disease risk factors. Pts provided their personal history, age, BMI, age of first pregnancy, BF, number of children breastfed, radiation exposure (RE), years of OCP use, benign breast disease (BD), hysterectomy, hormone replacement therapy (HRT) and rBC. The t-test and chi-square test were used for continuous and categorical variables, respectively. The association [adjusted odds ratio (aOR)] between rBC and each risk factor was obtained using logistic regression after adjusting for all the variables including stage of cancer.

Results:

A total of 2546 patients were surveyed, of which 218 patients had rBC later in life. The average age of pts with recurrence was 54 yrs and those without rBC was 56 yrs. Of the total, 73.5% had BF, 25% had used OCP, 17.3% used HRT, 5.6% had RE, 16.6% had a hysterectomy, and 16% had BD. In multivariate analysis, age, BF, OCP and RE each had significant impacts on the rBC. Pts who did not BF had a 3-fold increased risk of recurrence compared to those who breastfed at least 3 children [aOR of 2.9 (1.7-4.9)]. Pts who did not use OCPs were 53% less likely to have rBC compared to those who used OCPs [aOR of 0.47 (0.32-0.69)]. A statistically significant dose-effect for number of children breastfed and rBC, and years of OCPs usage and rBC was found. BMI, HRT, hysterectomy, BD, and age at first pregnancy did not have an effect on rBC.

Conclusion: Our study suggests that breastfeeding decreases the risk of recurrence of breast cancer, while OCP usage increases the risk of recurrence of breast cancer. Further studies are needed to validate our results.

Predictors of recurrence of breast cancer (rBC)Variablesβ EstimateAdjusted OR (CI)p-valueAge0.0221.02 (1.008-1.03)0.002Breastfed (BF, none vs. >3 children)1.062.9 (1.7-4.9)<0.0001Breastfed (BF, < 3 vs. > 3 children)0.742.09 (1.2-3.5)0.006Oral Contraceptive use (OCP, no vs. yes)-0.7430.47 (0.32-0.69)0.0001Radiation exposure (RE, no vs. yes)-1.310.26 (0.16- 0.13)<0.0001HRT (no vs. yes)0.41.49 (0.96-2.3)0.07

Citation Format: Teresa A. Lehman, Mohammed Shaik, Ramakrishna V. Modali, Borys Hrinczenko. Effects of breastfeeding and oral contraception use on the risk of breast cancer recurrence: A multinational study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 860. doi:10.1158/1538-7445.AM2015-860
Abstract 867: Reproductive factors and risk of B-cell non-Hodgkin lymphoma among women in Los Angeles
Authors: Lu Yani , Luo Jianning , Wang Sophia , Sullivan-Halley Jane , Cozen Wendy , Bernstein Leslie
Published: August 2015

Background: Overall, non-Hodgkin lymphoma (NHL) incidence is higher in men than women, and the male to female ratio differs by NHL subtype. Historically, female reproductive characteristics and patterns have been inconsistently linked to NHL risk, though studies on this topic remain limited. Because a woman experiences changes in immune function during pregnancy, that permit her to establish and maintain a successful pregnancy, we hypothesize that such pregnancy-associated changes in immune function could affect the risk of NHL, a cancer of the immune cells.

Methods: We conducted a population-based case-control study among women in Los Angeles County comprising 998 histologically confirmed B-cell NHL patients diagnosed 2004-2008 from the Los Angeles Cancer Surveillance Program and 998 individually matched controls (matched on age, race and socioeconomic status). Conditional logistic regression was used to calculate the associations [odds ratios (OR) and 95% confidence intervals (CI)] between female reproductive factors (e.g., ever pregnant; number of full-term pregnancies; breastfeeding) with B-cell NHL overall and unconditional logistic regression was used to calculate the associations with major NHL subtypes.

Results: Compared to women who had never been pregnant, women who had full-term pregnancies had 17% decreased risk of B-cell NHL (OR = 0.83, 95% CI = 0.64-1.08); the decreased risk was most pronounced for the diffuse large B-cell lymphoma (DLBCL) subtype (OR = 0.68, 95% CI = 0.47-0.98). Increasing number of full-term pregnancies was inversely associated with B-cell NHL overall (P-trend = 0.02), DLBCL (P-trend = 0.03) and follicular lymphoma (P-trend = 0.04). Women who had reported breastfeeding also had decreased risk of B-cell NHL overall (OR = 0.80, 95% CI = 0.64-1.00) and follicular lymphoma (OR = 0.71, 95% CI = 0.50-1.00). Among women who had full-term pregnancies, women who breastfed for 60 weeks or more had 30% decreased risk of B-cell NHL overall (OR = 0.70, 95% CI = 0.52-0.93; P-trend = 0.06), which was consistent for follicular lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Conclusions: Our results provide evidence for an association between female reproductive factors and decreased risk of B-cell NHL, supporting a role for hormonal factors in B-cell NHL etiology.

Citation Format: Yani Lu, Jianning Luo, Sophia Wang, Jane Sullivan-Halley, Wendy Cozen, Leslie Bernstein. Reproductive factors and risk of B-cell non-Hodgkin lymphoma among women in Los Angeles. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 867. doi:10.1158/1538-7445.AM2015-867
Abstract 869: Body mass index, weight gain, and physical activity during adulthood in relation to colorectal cancer risk
Authors: Tu Huakang , Pu Xia , Daniel-MacDougall Carrie , Melkonian Stephanie C. , Ye Yuanqing , Raju Gottumukkala S. , Kopetz Scott , Wu Xifeng
Published: August 2015

Background: The impact of obesity/overweight, weight gain, and physical activity during adulthood on colorectal cancer (CRC) risk is not clear. To examine the associations between body mass index (BMI), weight gain, and physical activity during adulthood and CRC risk, we conducted a case-control study of incident CRC.

Methods: Incident CRC case subjects were recruited from the University of Texas MD Anderson Cancer Center in Houston, Texas; healthy control subjects without a history of cancer, except non-melanoma skin cancer, were identified and recruited using random digit dialing. Epidemiologic data were collected by in-person interview. Unconditional logistic regression and regression spline were performed to obtain odds ratios (ORs). All statistical tests were two-sided.

Results: A total of 524 non-Hispanic white case subjects and 1,053 healthy control subjects who were 40 years or older were included. In multivariate analysis, obesity (BMI ≥ 30) and overweight (BMI between 25 and 30) at age 20 years were significantly associated with a 2.4-fold (OR = 2.39, 95% confidence interval [CI] = 1.38 - 4.13, P = .002) and 1.6-fold (OR = 1.60, 95% CI = 1.19 - 2.14, P = .002) increased risk of CRC, respectively. Similarly, obesity and overweight at age 40 years were each significantly associated with a 2.1-fold (OR = 2.11, 95% CI = 1.49 - 2.99, P < .0001) and 1.7-fold (OR = 1.74, 95% CI = 1.32 - 2.30, P < .0001) increased risk of CRC. In addition, moderate and massive weight gain from age 20 to 40 years were associated with increased CRC risks, although this increase did not reach statistical significance. Moderate physical activity was significantly associated with a reduced risk of CRC (OR = 0.60, 95% CI = 0.44 - 0.81, P = .001).

Conclusions: Obesity/overweight and physical activity during adulthood may influence susceptibility to CRC; also, our data suggest that weight gain during childhood and adolescence may play a more important role than weight gain during adulthood in CRC development.

Citation Format: Huakang Tu, Xia Pu, Carrie Daniel-MacDougall, Stephanie C. Melkonian, Yuanqing Ye, Gottumukkala S. Raju, Scott Kopetz, Xifeng Wu. Body mass index, weight gain, and physical activity during adulthood in relation to colorectal cancer risk. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 869. doi:10.1158/1538-7445.AM2015-869
Abstract 870: Physical activity, diet and ovarian cancer risk
Authors: Lehman Teresa A. , Modali Ramakrishna V. , Ratnasinghe Luke
Published: August 2015

Physical activity and diet are modifiable risk factors for most cancers. Previous studies of the association between physical activity, diet and ovarian cancer risk have yielded mixed results. We evaluated the association between physical activity, diet and ovarian cancer risk among 578 ovarian cancer cases and 7188 non-cancer controls in the Global Epidemiology Study (GES). The GES is linked to the Global Repository that houses biomaterial. For ovarian cancer, newly diagnosed subjects provided informed consent and were asked about physical activity and diet during in-person interviews. The multivariate-adjusted odds ratio (OR) was 0.6 (95% confidence interval (95% CI): 0.5-0.8) for women who reported physical activity greater than 160 minutes per week after adjusting for age, race, BMI and pack-years of smoking compared to women who reported less than 30 minutes of physical activity. Women who were in the highest tertile of vegetables consumers were at 20% reduced risk for ovarian cancer compared to the lowest tertile [OR:0.8, 95% CI: 0.6-0.9]. Individuals who were in the highest tertile of dairy consumers were at 40% reduced risk for ovarian cancer compared to the lowest tertile [OR: 0.6, 95% CI: 0.5-0.8]. For meat consumption, individuals who were in the highest tertile were at 60% increased risk for ovarian cancer compared to the lowest tertile [OR: 1.6, 95% CI: 1.3-2.0]. Results from our study suggest that physical activity and diet are modifiable risk factors for ovarian cancer.

Citation Format: Teresa A. Lehman, Ramakrishna V. Modali, Luke Ratnasinghe. Physical activity, diet and ovarian cancer risk. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 870. doi:10.1158/1538-7445.AM2015-870
Abstract 871: The association between periodontal disease and pancreatic cancer
Authors: Chang Jeffrey S. , Tsai Chia-Rung , Shan Yan-Shen , Chen Li-Tzong
Published: August 2015

Background: Despite years of research, the causes of pancreatic cancer have remained largely unknown. Periodontal disease (PD) is an emerging risk factor for various systemic diseases, including cancer. The current study investigated the association between PD (periodontitis, gingivitis, and others) and development of pancreatic cancer.

Methods: Using data from the National Health Insurance Research Database of Taiwan, 139,805 subjects with PD and 75,085 subjects without PD were identified. The association between PD and pancreatic cancer was assessed using Cox proportional hazards regression model.

Results: Having PD was associated with a higher pancreatic cancer risk (hazard ratio (HR) = 1.55, 95% confidence interval (CI): 1.02-2.33). The higher pancreatic cancer risk associated with PD was observed among those aged 65 years or older (HR = 2.17, 95% CI: 1.03-4.57) and but not among those aged younger than 65 years (HR = 0.83, 95% CI: 0.52-1.34). Further analysis showed that PD remained an independent risk factor for pancreatic cancer after adjusting for diabetes, hyperlipidemia, allergies, viral hepatitis, peptic ulcer, pancreatitis, COPD (as a proxy for cigarette smoking) and alcoholic-related conditions (as a proxy for alcohol drinking).

Conclusions: Our analysis showed a significantly positive association between PD and pancreatic cancer risk. Further investigation is needed to explain the underlying biological mechanisms for the positive association between PD and pancreatic cancer.

Citation Format: Jeffrey S. Chang, Chia-Rung Tsai, Yan-Shen Shan, Li-Tzong Chen. The association between periodontal disease and pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 871. doi:10.1158/1538-7445.AM2015-871
Abstract 875: Risk factors for hepatocellular carcinoma (HCC) by race/ ethnicity in the United States
Authors: Makarova-Rusher Oxana V. , Altekruse Sean F. , McNeel Timothy S. , Graubard Barry I. , Duffy Austin G. , Ulahannan Susanna V. , Greten Tim F. , McGlynn Katherine A.
Published: August 2015

Background: Primary liver cancer is the sixth most common cancer worldwide, with HCC representing the majority of the cases. In the U.S., HCC rates are higher among Hispanics, Asians and blacks than among whites. Whether the higher risks are due to different distributions of risk factors is not clear. Thus, we conducted an analysis of HCC risk factors by race/ethnicity in the SEER-Medicare database for the years 2000-2009.

Methods: HCC cases (n = 8,116), identified by ICD-O morphology codes 8170-8175, were compared to a 5% random sample of cancer-free persons in the SEER areas (n = 313,525). Risk factors examined included type II diabetes (DM II), obesity, hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol-related disorders. Multivariate logistic regression analyses, which adjusted for age, location, gender, income and date of diagnosis as well as the other risk factors were used to compare risk factors by racial/ethnic group.

Results:

Risk factors by race/ethnicity

Risk factorWhiteBlackAsiansHispanicsN 6,120N 668N 971N 357%OR (95% CI)%OR (95% CI)%OR (95% CI)%OR (95% CI)Obesity6.31.06 (0.9-1.2)5.51.0 (0.7-1.5)0.70.2 (0.1-0.8)7.81.2 (0.7-1.9)DM II44.52.9 (2.8-3.1)41.81.3 (1.1-1.6)38.11.8 (1.5-2.1)54.62.0 (1.5-2.7)HBV1.83.8 (2.6-5.7)3.61.6 (0.7-3.7)17.717.1 (11.8-25.0)2.01.4 (0.2-11.1)HCV16.819.7 (17.1-22.6)34.036.8 (28.0-48.6)31.121.4 (15.4-29.9)22.716.0 (9.2-28.1)Alcohol cirrhosis11.44.7 (3.7-5.8)7.64.5 (2.4-8.5)4.03.8 (1.3-11.7)17.13.3 (1.7-6.8)Alcohol NOS13.12.7 (2.2-2.9)13.21.6 (1.1-2.4)3.72.0 (1.0-4.1)14.81.6 (0.8-3.0)Cirrhosis NOS33.345.5 (41.2-50.4)24.117.9 (12.3-25.9)36.836.9 (26.2-52.0)44.827.6 (18.9-40.3)

NOS not otherwise specified.

Conclusion: Major HCC risk factor profile is differ across race/ethnical groups. While diabetes is most common risk factor overall, it is most prevalent in Hispanics. HCC related to HCV is more common in blacks and Asians, and to HBV in Asians.

Citation Format: Oxana V. Makarova-Rusher, Sean F. Altekruse, Timothy S. McNeel, Barry I. Graubard, Austin G. Duffy, Susanna V. Ulahannan, Tim F. Greten, Katherine A. McGlynn. Risk factors for hepatocellular carcinoma (HCC) by race/ ethnicity in the United States. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 875. doi:10.1158/1538-7445.AM2015-875
Abstract 88: The Nkx3.1 homeobox gene maintains prostatic identity while its loss leads to prostate cancer initiation
Authors: Le Magnen Clémentine , Dutta Aditya , Abate-Shen Cory
Published: August 2015

Background

Maintenance of epithelial cell identity is tightly coordinated by tissue-specific gene expression programs, which are often deregulated during tumorigenesis. The homeodomain-containing transcription factor, Nkx3.1, is a key regulator of normal prostatic development and is frequently lost at early stages of prostate cancer initiation. In this study, we aim to elucidate detailed mechanisms governing Nkx3.1-driven maintenance of prostate identity and how deregulation of such can lead to prostate tumorigenesis.

Models and Methods

We evaluated the consequences of Nkx3.1 loss or gain of function in vivo using genetically-engineered mouse models and cell-recombination assays. RNA sequencing was performed to generate gene expression profiles, which were analyzed using Gene Set Enrichment analysis (GSEA), and validated by quantitative real-time PCR. In parallel, protein expression was assessed by immunofluorescence and western blot. Immunoprecipitation (IP) and chromatin-immunoprecipitation (ChIP) assays were performed using RWPE1 prostate epithelial cells.

Results

Here, we show that loss of function of Nkx3.1 leads to the progressive down-regulation of a prostate-specific gene expression program and to aberrant expression of genes that are not typically expressed in the prostate epithelium. Conversely, gain of function of Nkx3.1 in non-prostatic epithelium leads to the acquisition of a prostate-like morphology and expression of prostate-related genes. Our findings indicate that the underlying mechanism by which Nkx3.1 promotes prostatic identity is via epigenetic regulation of gene expression. In particular, we show that Nkx3.1 interacts with the histone methyl-transferase complex G9a/Glp. Finally, we demonstrate that this interaction is necessary for maintenance of prostate identity in vivo and that Nkx3.1 and G9a cooperate to control expression of genes that coordinate prostatic epithelial integrity.

Conclusions

Our results suggest that Nkx3.1 promotes prostatic identity by interacting with histone modifying enzymes to coordinate the expression of prostate-specific genes and that the loss of this function results in a failure to maintain prostate identity associated with early stages of prostate tumorigenesis.

Citation Format: Clémentine Le Magnen, Aditya Dutta, Cory Abate-Shen. The Nkx3.1 homeobox gene maintains prostatic identity while its loss leads to prostate cancer initiation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 88. doi:10.1158/1538-7445.AM2015-88
Abstract 883: Body mass, smoking habit, and hypertension and renal cell cancer survival
Authors: Lee Jung Eun , Kim Nayeon , Adami Hans-Olov , Lindblad Per
Published: August 2015

Background: A recent meta-analysis showed higher survival rate among over-weight and obese renal cell cancer (RCC) patients. Given that obesity, smoking and hypertension are well-established risk factors for RCC development, it is therefore important to know whether these factors are associated with RCC prognosis.

Objectives: We evaluated the associations of body mass index (BMI), smoking and hypertension with RCC survival in a population-based cohort of incident RCC cases assembled from a Swedish case-control study.

Methods: We analyzed a total of 371 RCC cases diagnosed in 1988-1992 with follow-up through Dec 31, 2011. Information on weight, height, smoking habit and hypertension was obtained through face-to-face interviews. Mortality information was determined through linkage to the National Cancer Registry; 298 deaths were identified, with 148 of those having RCC as the underlying cause of death, during an average of 9.9 years of follow-up. We calculated hazard ratios (HR)s and 95% confidence interval (CI)s using the Cox proportional hazards models.

Results: We confirmed that lifetime smoking and BMI at highest adult weight were associated with a worse overall survival among RCC patients. When we examined RCC-specific survival, the associations were not statistically significant; multivariate HR (95% CI) was 0.89 (0.54-1.49) for 20 or greater pack-years of smoking compared to never smokers. For BMI at highest adult weight, multivariate HR (95% CI) was 0.99 (0.53-1.87) comparing 35 or greater levels of BMI with less than 27 kg/m2 of BMI. History of hypertension was not associated with overall or RCC-specific survival.

Conclusions: We found a decreasing trend of overall survival with increasing prediagnostic BMI and lifetime smoking, but no significant associations of these factors and hypertension with RCC-specific survival among RCC patients.

Citation Format: Jung Eun Lee, Nayeon Kim, Hans-Olov Adami, Per Lindblad. Body mass, smoking habit, and hypertension and renal cell cancer survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 883. doi:10.1158/1538-7445.AM2015-883
Abstract 886: Health behaviors of cancer survivors: higher alcohol drinking, lower smoking and physical inactivity pattern in survivors with higher household income
Authors: Park Boyoung , Kong Sun-Young , Kim Jeongseon , Kim Yeol , Park In Hae , Jung So-Youn , Lee Eun Sook
Published: August 2015

Background: This study investigated the prevalence of smoking, alcohol consumption, and physical activity in cancer survivors and examined the sociodemographic factors affecting these health-related behaviors.

Methods: We used data from the fourth and fifth Korean National Health and Nutrition Examination Survey conducted between 2007 and 2012, which identified 1,153 cancer cases and 34,368 non-cancer controls ≥ 20 years of age. We used a structured questionnaire to obtain information concerning cancer diagnosis and sociodemographic characteristics.

Results: The proportion of cancer survivors who were current drinkers, heavy drinkers, current smokers, or engaged in physical activity were 49.1, 9.0, 9.2, or 50.7%, respectively. Compared with non-cancer controls, cancer survivors were less likely to be current drinkers, heavy drinkers, or current smokers (odds ratio [OR] = 0.56; 95% confidence interval [CI], 0.47-0.66; OR = 0.58; 95% CI, 0.44-0.78; and OR = 0.44, 95% CI, 0.34-0.59, respectively). Cancer survivors with higher household incomes had higher odds of current drinking and heavy drinking (P trend = 0.04 and 0.03, respectively) and were less likely to be current smokers or physically inactive (P trend <0.01 and 0.03, respectively). Age, gender, employment status, the type of cancer, and the duration of cancer diagnosis affected the health behaviors. Furthermore, we confirmed that these unhealthy behaviors are interrelated. Conclusions: We found that household income had a bidirectional effect on health behaviors and confirmed an aggregation of unhealthy lifestyles. Identification of survivors vulnerable to unhealthy lifestyles would allow intervention programs to be more effective.

Citation Format: Boyoung Park, Sun-Young Kong, Jeongseon Kim, Yeol Kim, In Hae Park, So-Youn Jung, Eun Sook Lee. Health behaviors of cancer survivors: higher alcohol drinking, lower smoking and physical inactivity pattern in survivors with higher household income. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 886. doi:10.1158/1538-7445.AM2015-886
Abstract 89: Pin1 suppresses androgen receptor activity
Authors: Van der Steen Travis , Huang Haojie , Tindall Donald
Published: August 2015

Reactivation of the androgen receptor (AR) is the hallmark of prostate cancer (PCa) progression to the castration resistant prostate cancer (CRPC) phenotype. Currently, treatment for CRPC strives to impede the full-length AR (AR-FL) from becoming activated through targeting the ligand binding domain (LBD) via androgen deprivation therapy or treatment with antiandrogens. However, these options can give rise to AR-variants (AR-Vs) that lack the LBD and are unresponsive to treatment. Therefore, targeting the N-terminus of AR, which is conserved between AR-FL and AR-Vs, is critical for identifying new treatment options. Phosphorylation of serine 81 (AR-pS81) in the N-terminus of AR is critical for AR activation, stability and recruitment to the chromatin. Similar phosphorylation sites can be observed in the N-terminus of both AR-FL and AR-Vs. Expression of Pin1, a proline isomerase, exhibits a strong correlation with progression and relapse of PCa. Also, suppression of Pin1 in PCa decreases cell proliferation rates, suggesting that Pin1 may play a pivotal role in PCa progression. Pin1 isomerizes proline residues from trans to cis when the adjacent serine/threonine residue is phosphorylated. Dephosphorylation by phosphatases occurs when a pS-P motif is in the trans conformation. Therefore, Pin1 isomerization of AR pS81-P82 from trans to cis could prevent dephosphorylation and result in constitutive or enhanced AR activity. Stable cell lines with Pin1 knockdown were generated via shRNA targeting the 5′ UTR of Pin1 that express either AR-FL and/or AR-Vs. Pin1 knockdown was confirmed by western blots, and AR activity was monitored by expression of several AR regulated genes. Additionally, AR recruitment to chromatin was assayed by ChIP and Re-Chip. Loss of Pin1 resulted in a 60% reduction of endogenous PSA expression, and AR was unable to induce PSA expression when treated with androgens. However, suppression of AR activity was not due to decreased recruitment of AR to chromatin. Phosphorylation of AR-pS81 was decreased by loss of Pin1, while protein stability and mRNA expression was not altered. These data suggest that Pin1 may play a critical role in regulating the transcriptional activity of AR by altering the accessibility of AR to interact with transcriptional machinery needed to maintain AR activity. (Funding for this project was provided by the T.J. Martell Foundation).

Citation Format: Travis Van der Steen, Haojie Huang, Donald Tindall. Pin1 suppresses androgen receptor activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 89. doi:10.1158/1538-7445.AM2015-89
Abstract 891: FGF21 prevents high fat diet-induced pancreatic cancer in mice expressing oncogenic Kras
Authors: Lu Weiqin , Yang Yaying , Wang Xiaojie , Liu Yan , Luo Yongde , Wolff Robert A. , Abbruzzese James L. , Logsdon Craig D.
Published: August 2015

The genetic landscape of pancreatic cancer shows nearly ubiquitous mutations of Kras. However, expression of mutant Kras alone is not sufficient to drive pancreatic ductal adenocarcinoma (PDAC) in adult mice. Obesity is a metabolic disorder and is a risk factor for PDAC. One of the main factors that contributes to the development of obesity is high-fat consumption. Recent studies have demonstrated that High-Fat-Diet (HFD) can promote oncogenic Kras mediated development of pancreatic intraepithelial neoplasia and PDAC. However, it is not clear why mice with oncogenic KrasG12D expression are predisposed to HFD mediated pancreatic carcinogenesis. Here, we report that Ras activity dramatically reduces the expression of fibroblast growth factor 21 (FGF21). FGF21 is a key mediator of fatty acid oxidation and lipid metabolism. Pharmacological doses of FGF21 lower serum free fatty acids and lead to weight loss in obese mice. FGF21 is highly expressed in pancreatic acinar cells and is a potential autocrine factor. High levels expression of FGFR1 and β-Klotho, key components for specific sites of FGF21 action, were observed on normal control mouse pancreatic acinar cells using both qRT-PCR and immunohistochemistry technics. FGF21 levels were dramatically reduced (∼6-fold) by Cre-mediated knock-in of oncogenic KrasG12D within one week and further decreased by more than 100-fold within 7 months. This effect of KrasG12D may have been mediated by decreased expression of pancreatic transcription factor Mist1, which was also observed. To dissect obesity and oncogenic KrasG12D mediated PDAC, we fed adult KrasG12D expressing mice with HFD or HFD+FGF21. We observed that KrasG12D expressing mice fed with HFD+FGF21 for 9 weeks significantly lower body weight and pancreatic triglyceride, as well as dramatically fewer PanIN lesions and tumor, compared with KrasG12D mice on a HFD without FGF21. FGF21 treatment extended survival of KrasG12D expressing mice on a HFD. Our results suggest that pancreas-derived FGF21 is an important metabolic regulator which is silenced by oncogenic KrasG12D expression and plays an important role in preventing HFD induced PDAC in KrasG12D expressing mice.

Citation Format: Weiqin Lu, Yaying Yang, Xiaojie Wang, Yan Liu, Yongde Luo, Robert A. Wolff, James L. Abbruzzese, Craig D. Logsdon. FGF21 prevents high fat diet-induced pancreatic cancer in mice expressing oncogenic Kras. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 891. doi:10.1158/1538-7445.AM2015-891
Abstract 893: Metabolomic profiling of APCΔ14/+ mice maintained on a methyl donor deficient diet reveals alterations to methionine and fatty acid metabolism associated with cancer protection
Authors: Hanley Matthew P. , Rosenberg Daniel W.
Published: August 2015

Our laboratory has previously demonstrated that administration of a diet deficient in methyl donor nutrients (folic acid, methionine, choline and vitamin B12) reduces tumor multiplicity by greater than 95% in ApcMin/+ mice. However, the mechanism by which this dramatic cancer protection is afforded is unknown. To begin to identify the metabolic consequences of methyl donor deficiency, we have conducted an LC/MS-based metabolic profiling analysis of colonic mucosa collected from ApcΔ14/+ mice fed a methyl donor deficient (MDD) diet for 17 weeks. Methyl donor deficiency causes significant alterations to a number of key metabolic pathways, including those involved in the methionine cycle, fatty acid oxidation, and tryptophan catabolism. We observed significant reductions in methionine (65% reduction, p<0.001) and betaine (70% reduction, p<0.001), accompanied by large increases in homocysteine (88.6-fold increase, p<0.001) and S-adenosylmethionine (17.2-fold increase, p<0.001), confirming that dietary methyl donor deficiency alters one-carbon metabolites in the colon. MDD mice were found to have reduced levels of acyl-carnitines and free carnitine (58% reduction, p<0.001). Additionally, we detected a reduction in the critical metabolic component, acetyl CoA, suggesting decreased transport of fatty acids into the mitochondria for use in fatty acid oxidation (FAO). Finally, we observed changes in the mucosal levels of tryptophan (32% reduction, p = 0.02), kynurenine (2.8-fold increase, p = 0.008) and indolepropionate (5.1-fold increase, p = 0.005), that were retained for seven weeks beyond active methyl donor deficiency. Taken together, these findings suggest that dietary methyl donor deficiency significantly disrupts the methionine cycle, inhibits fatty acid transport and oxidation, and may induce long-term changes to tryptophan metabolism. This study has improved our understanding of the molecular mechanisms underlying the cancer protection conveyed by dietary methyl donor deficiency and has identified metabolic pathways that are candidate targets for chemopreventive intervention.

Citation Format: Matthew P. Hanley, Daniel W. Rosenberg. Metabolomic profiling of APCΔ14/+ mice maintained on a methyl donor deficient diet reveals alterations to methionine and fatty acid metabolism associated with cancer protection. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 893. doi:10.1158/1538-7445.AM2015-893
Abstract 904: Lifetime genistein alters mammary tumors’ response to anti-estrogen tamoxifen treatment by affecting immune function in rats
Authors: Zhang Xiyuan , Cook Katherine , Hilakivi-Clarke Leena
Published: August 2015

Consistent with the human data showing that soy intake reduces the risk of breast cancer recurrence, we have previously reported that childhood and lifelong genistein (GEN) intake enhanced response of mammary tumors to tamoxifen (TAM) treatment and prevented recurrence in rats. Mammary tumor recurrence was also inhibited by starting GEN consumption in adulthood. Since GEN is shown to alter immune functions, and tumor immune responses can determine cancer outcome, we examined several immune markers in the tumor prior to TAM treatment.

Female Sprague-Dawley rats were fed control AIN93G diet or AIN93G diet supplemented with 500 ppm GEN either during childhood (between postnatal days 15 and 30), adulthood (from 55 days to end of the study), or both. Mammary tumors were induced by DMBA at the age of 48 days, and when a tumor reached a size of 1.4 cm in diameter (criteria for starting TAM treatment in the previous study), rats were euthanized (n = 15 per group), and blood and mammary tumors were collected.

We determined the expression of CD8-alpha (present in cytotoxic T lymphocytes) and Foxp3, TGFβ1 and TGF2 (present in regulatory T-cells, Treg) in mammary tumors from rats with varying lifetime exposures to GEN. Compared with the control rats, expression of CD8-alpha mRNA was significantly increased by GEN intake at any time during the life cycle, suggesting an elevation in cytotoxic T-cells density infiltrating the tumor. Foxp3 and TGF-β1 mRNA were significantly reduced by GEN consumption. Increased Treg levels in tumors result in the suppression of immune responses; therefore, a reduction in Foxp3 and TGF-β1 may indicate a decrease in immune suppression. TGF-2 mRNA expression was significantly increased in the tumors of rats that consumed GEN only as adults. In the serum, interleukin (IL)-1 and IL-6 levels were significantly elevated in rats that consumed GEN only during childhood, whilst IL-6 was reduced in rats consuming GEN during lifetime or only as adults. IL-12 that is reported to stimulate cellular immunity, was increased in the rats that consumed GEN during lifetime or as adults.

Our findings suggest that the ability of GEN intake to prevent mammary cancer recurrence is associated with improved immune responses in the tumor.

Citation Format: Xiyuan Zhang, Katherine Cook, Leena Hilakivi-Clarke. Lifetime genistein alters mammary tumors’ response to anti-estrogen tamoxifen treatment by affecting immune function in rats. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 904. doi:10.1158/1538-7445.AM2015-904
Abstract 909: Mechanistic study of synergistic interaction between genistein and equol in MCF-7 human breast cancer cells in vitro
Authors: ONO MISAKI , EJIMA KAORU , TAKESHIMA MIKAKO , HIGUCHI TAKAKO , WAKIMOTO REI , NAKANO SHUJI
Published: August 2015

Soy isoflavones, such as genistein, daidzein, glycitein and equol, a metabolite of daidzein, have been suggested to affect the growth of estrogen-receptor positive breast cancer cells in vitro, and thus considered to be involved in the prevention of breast cancer. We have recently reported that soy isoflavone component mixture has a greater preventive activity against breast cancer rather than genistein alone using chemically induced rat model of hormone-dependent mammary carcinoma. Therefore, we investigated here whether a synergistic interaction exists between genistein and other isoflavone components in estrogen receptor positive MCF-7 cells. Effects of genistein in combination with other isoflavone components on proliferation, apoptosis, cell cycle perturbation, and signal proteins for survival, proliferation, and apoptosis were evaluated by WST-1 assay, FACS analyses, and Western blotting. Synergistic anti-proliferative activity of genistein was observed in combination with three respective isoflavone components, with the most efficacious interaction observed in combination with equal. In FACS study, cells were arrested at the G2/M by genistein but G1/S by equol. However, when these components were combined, cells were arrested at the G2/M, indicating a dominant effect of genistein over equol. Although apoptosis was not evident when cells were treated with either genistein or equol alone, combination treatment markedly induced apoptosis, with demonstrable cleavage of PARP. Upon combination treatment, constitutive activities of Erk1/2 were enhanced, but those of Akt were significantly inhibited, with subsequent reductions of activities of downstream mTOR. Reduced expression of anti-apoptotic Bcl-xL and enhanced expression of proapoptotic Bax were also demonstrated. These data indicate that synergic mechanism of genistein in combination with equol would be mediated by enhanced apoptosis induction through inactivation of Akt and its downstream molecule mTOR, followed by subsequent upregulation of Bax and downregulation of Bcl-xL, thus providing mechanistic rationale for soy isoflavone for the prevention of human breast cancer.

Citation Format: MISAKI ONO, KAORU EJIMA, MIKAKO TAKESHIMA, TAKAKO HIGUCHI, REI WAKIMOTO, SHUJI NAKANO. Mechanistic study of synergistic interaction between genistein and equol in MCF-7 human breast cancer cells in vitro. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 909. doi:10.1158/1538-7445.AM2015-909
Abstract 912: Sulforaphane suppresses the growth of triple-negative breast cancer stem-like cells in vitro and in vivo
Authors: Castro Nadia P. , Rangel Cristina M. , Salomon David , Saylor Karen , Kim Young S.
Published: August 2015

Approximately 10-20% of breast cancer consists of triple-negative tumors, which present the poorest prognosis among the different subtypes. The triple-negative breast cancer (TNBC) tumors are known to be enriched with stem-like cells that are resistant to standard targeted drugs. Thus, it is extremely important to develop new agents that are non-toxic and specifically efficacious against these cancer stem-like cells (CSCs) that are suggested to be responsible for the initiation and maintenance of tumors. Here, we show that sulforaphane (SFN), a dietary component abundant in broccoli and broccoli sprouts, inhibits cell proliferation and sphere formation of the CSC population in TNBC cells.

TNBC stem-like cells were isolated from MDA-MB-231 Luci D3H1human triple negative breast cancer cells using fluorescently activated cell sorting (FACS) analysis. Six week old BalbC/nude mice were purchased from Jackson laboratory and fed with an AIN-96G-purified diet containing no SFN (Harlan Teklad Inc) until the end of experiments. The mice (n = 40) were treated with or without daily i.p. injection of 50mg SFN/kg b.w. for 2 weeks prior to the inoculation with MDA-MB-231 Luci D3H1 cells. The tumor cells were planted into both sides of the 4th inguinal mammary fat pads. The SFN treatment was continued for 3 additional weeks after the tumor cell xenografts.

Our results revealed that the CSC population isolated with CD49f+, CD24-/CD44high showed the ability to form mammoshperes, which is a characteristic of stemness. When these cells were treated with natural dietary constituent SFN at the concentration of 7.5 μM, they lost the property of mammosphere formation in vitro. Furthermore, SFN pre-treated animals (n = 20) exhibited a thirty percent reduction in tumor volume compared with control (saline 0.9%) at day 30 after the tumor cell inoculation. These data indicate that SFN suppresses triple negative mammary tumor formation both in vitro (7.5uM) and in vivo (50mg/kg bw) by targeting a CSC population. Further analysis on gene expression and protein profiles are being performed to elucidate whether stem-related developmental signaling pathways are being modulated by SFN.

Citation Format: Nadia P. Castro, Cristina M. Rangel, David Salomon, Karen Saylor, Young S. Kim. Sulforaphane suppresses the growth of triple-negative breast cancer stem-like cells in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 912. doi:10.1158/1538-7445.AM2015-912
Abstract 920: Mechanism of the transferrin receptor 1 dysregulation in hepatocarcinogenesis
Authors: Kindrat Iryna , Tryndyak Volodymyr , de Conti Aline , Shpyleva Svitlana , Erstenyuk Anna , Beland Frederick A. , Pogribny Igor
Published: August 2015

Hepatocellular carcinoma (HCC) is one of the most prevalent life-threatening human cancers, with a rapidly increasing incidence worldwide. The pathogenesis of HCC is complex and consists of multiple interconnected molecular alterations. Current evidence indicates that altered iron metabolism plays an important role in the development and progression of HCC; however, there is a lack of conclusive information regarding the mechanisms of this dysregulation. In previous studies using different models of rodent carcinogenesis, we demonstrated prominent alterations of intracellular iron metabolism in preneoplastic livers, including changes in gene expression and the level of related proteins involved in the regulation of intracellular hepatic iron metabolism, primarily up-regulation of transferrin receptor 1 (TFRC). In the present study, we investigated the role and underlying mechanisms of the aberrant expression of TFRC, the main receptor controlling cellular iron uptake, in liver carcinogenesis. In both preneoplastic liver tissue from a relevant rat model of human HCC and in human HCC cells, there was a significant increase in the levels of TFRC mRNA and protein. This resulted in a substantial increase in TFRC/ferroportin (FPN) ratio, favoring an accumulation of iron in the HCC cells. The increase in levels of TFRC was attributed to a post-transcriptional microRNA-mediated mechanism. This was demonstrated by a computational analysis and confirmed experimentally by in vitro transfection experiments showing that transfection of human HCC cell lines with has-miR-152 effectively suppressed the expression of TFRC. Additionally, there was a strong inverse correlation between the level of TRFC and the expression of miR-152 in human HCC cells (r = -0.99, p = 4.7×10-9). Finally, the expression of TFRC and miR-152 in human HCC tissues was evaluated using the TCGA database. We observed an over-expression of TFRC in human HCC tissue samples and a markedly decreased level of miR-152 when compared to non-tumor liver tissue. These results demonstrate that dysregulation of cellular iron metabolism in liver carcinogenesis is driven by an up-regulation of TFRC, and indicate that miR-152-specific targeting of TFRC to decrease its levels may provide a selective anticancer therapeutic approach for the treatment of HCC.

Citation Format: Iryna Kindrat, Volodymyr Tryndyak, Aline de Conti, Svitlana Shpyleva, Anna Erstenyuk, Frederick A. Beland, Igor Pogribny. Mechanism of the transferrin receptor 1 dysregulation in hepatocarcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 920. doi:10.1158/1538-7445.AM2015-920