bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 594: Effect of caloric restriction and high fat diet on azoxymethane-induced carcinogenesis in LETO and OLETF rats
Authors: Takasu Chie , Takahashi Tetsuyuki , Izumi Keisuke
Published: August 2012

We showed recently that diabetic and mildly obese Otsuka Long-Evans Tokushima Fatty (OLETF) rats are more susceptible to azoxymethane (AOM)-induced Zymbal gland and intestinal carcinogenesis than control Long-Evans Tokushima Otsuka (LETO) rats. In the present study, we examined the effect of caloric restriction (CR) and high-fat diet (HFD) on AOM-induced carcinogenesis in these strains. Experiment 1: Six-week-old male LETO and OLETF rats (n=21) were given s.c. injections of 15 mg/kg AOM once weekly for 3 weeks, then fed, Group 1) control diet, Group 2) 20% CR diet, or Group 3) HFD (control diet with 10% safflower oil), and killed at 36 weeks of age. In LETO rats, the incidences of colon tumors (adenoma plus adenocarcinoma) in Groups 1-3 were 45%, 33% and 55%, respectively. Average number of tumors/rat in CR group was fewer than that in HFD group (P<0.05). In OLETF rats, the incidences of colon tumors in Groups 1-3 were 76%, 48% and 62%, respectively. Zymbal gland tumors in CR group developed later than those in control and HFD groups in OLETF rats. Experiment 2: Male LETO and OLETF rats (n=5) were fed control diet, 20% CR diet or HFD for 5 weeks, and killed at 24 weeks of age. In LETO rats, serum triglyceride, total cholesterol, insulin and leptin levels decreased by 20% CR, and increased by HFD compared to the control group. In OLETF rats, those levels decreased by 20% CR, and increased by HFD except leptin. Expression of hepatic IGF-1 and Sirt-1 mRNA elevated by 20% CR in both strains. The liver of OLETF rat HFD group showed severe fatty change histologically. In conclusion, 20% CR inhibited, and HFD promoted colon carcinogenesis in LETO rats. In OLETF rats, 20% CR inhibited, but HFD did not promote colon carcinogenesis because of early development of Zymbal gland tumors. Hyperinsulinemia and/or hyperlipidemia may exert the promoting effect in rat carcinogenesis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 594. doi:1538-7445.AM2012-594
Abstract 6: Investigating the functional significance of FGFR2 SNP status in breast cancer
Authors: Robbez-Masson Luisa , Grose Richard
Published: August 2012

Familial Breast cancer is now seen as a polygenic disease. Although several major susceptibility genes, including BRCA1 and BRCA2, have been identified in several cases, breast cancer susceptibility seems to arise from a large number of genetic loci, each conferring a minor influence on overall risk. Recent genome-wide association studies (GWAS), have identified several SNPs that associate with increased risk of breast cancer. Some of the most significant are located in the second intron of the fibroblast growth factor receptor 2 (FGFR2) gene, indicating that the association with breast cancer is mediated through regulation of FGFR2. Functional SNPs within this region map to binding sites for the transcription factors Oct-1, Runx2 and C/EBPβ. Preliminary studies have shown that the Runx2 site is functional only in the minor, disease associated allele, resulting in increased expression of FGFR2 in cancer from patients homozygous for that allele. Moreover, the increased risk conferred by the minor FGFR2 allele is associated most strongly with ER+ breast tumours, suggesting a potential interaction between the two pathways. Our approach is to study the functional role of this new risk locus on the biology of cancer at the regulatory level. To study allele-specific gene expression (ASGE), we are using two surrogate SNP markers in the coding region of FGFR2, rs755793 and rs1047100. Taqman analysis of cDNA and genomic DNA from a panel of breast cancer samples allow us to evaluate the degree of SNP-dependent differential expression in a high throughput manner. Thus our study ultimately will allow us to test the hypothesis that the disease-associated allele of rs2981578 increases FGFR2 expression. Additionally, a genome editing approach using Zinc Finger Nucleases (ZFN) allows us to target the putative ‘regulatory’ SNP in breast cancer cell lines. A change, as small as a single nucleotide, can be made on MFC7 cell line to create new in vitro models that only differ in SNP status. These cell based models will be crucial in the study of the influence of FGFR2 SNPs in tumour initiation and progression. Thus our study will allow for the first time, investigation of the true physiological function of SNP status on breast cancer cell line behaviour.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 6. doi:1538-7445.AM2012-6
Abstract 604: The ginger compound, 6-shogaol, inhibits prostate cancer cell growth through reduced activation of signal transducer and activator of transcription 3 (Stat3)
Authors: Saha Achinto , Silver Eric S. , Sessler Jonathan L. , DiGiovanni John
Published: August 2012

Prostate cancer is the most common non-skin neoplasm and second leading cause of death in men in the USA with an estimated 240,890 new cases and 33,720 deaths from this disease in 2011. The risk for developing prostate cancer increases with age and overall 1 in 6 men will be diagnosed with this disease. Despite much recent progress, prostate cancer continues to represent a major cause of cancer-related mortality and morbidity in men. Ginger (Zingiber officinale) has been widely used as a spice, and as a medicinal herb in traditional herbal medicine. It is a natural dietary ingredient with antioxidant, anti-inflammatory, and anticarcinogenic properties. Ginger contains several pungent constituents such as gingerols, shogaols, paradols, and gingerdiols. The shogaols are predominant constituents in the dried ginger. Several studies reported that 6-shogaol has anticancer and anti-inflammatory activity. However the mechanism(s) involved in anticancer effect of 6-shogaol has not been clearly elucidated. In the current study, we found that 6-shogaol inhibited the proliferation of human prostate cancer cells including LNCap, DU145 and PC-3 in a concentration dependent manner. In order to find the mechanism associated with the antiproliferative effect of 6-Shogaol, we performed Western blotting and found that this compound inhibited the constitutive (DU145) and IL-6 (LNCap and DU145) induced phosphorylation of Stat3(Tyr705). 6-shogaol also inhibited constitutive and IL-6 induced phosphorylation of Stat3(Ser727) in both cell lines. It also decreased the level of several Stat3 regulated molecules such as cyclin D1 and survivin. Next we measured the apoptosis inducing activity of 6-shogaol and found that this compound induced apoptosis in LNCap and DU145 cells also in a concentration dependent manner. In order to confirm the mechanism involved in apoptosis induction, we measured the level of various apoptosis markers and found that 6-shogaol induced cleavage of PARP and caspase7 in both LNCap and DU145 cell lines. Quantitative real time PCR data showed that 6-shogaol decreased the mRNA level of Bcl2, CCL5, IL-6, IL-7 and increased the expression of Bax, p21, IRF1 and SOCS1. Collectively, the current data lead us to suggest that 6-shogaol may possess properties for further consideration as a therapeutic and/or chemopreventive agent for human prostate cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 604. doi:1538-7445.AM2012-604
Abstract 606: Inhibitory effects of piceatannol on tumor angiogenesis and lung metastasis in the 4T1 mammary cancer model
Authors: Song Hyerim , Kim Eun Ji , Park Jung Han Yoon
Published: August 2012

Piceatannol (trans-3,4,3′,5′-tetrahydroxystilbene) is a polyphenol found in Rheum undulatum, grapes, red wine, and berries and has been shown to exert anticarcinogenic effects. In the present study, we determined whether oral administration of piceatannol inhibits solid tumor growth, angiogenesis, and lung metastasis of mammary cancer cells. 4T1 cells (5 x 104 cells) were injected into the mammary fat pad of syngeneic, 6-week old, female BALB/c mice. One day after, the mice were subjected to gavage for 30 days with piceatannol (0, 10, or 20 mg/kg body weight/day). Oral piceatannol treatment induced a significant reduction in the growth of solid tumors. Immunohistochemical staining of tumor tissues revealed that the expression of Ki67 (prototypic cell cycle related nuclear antigen), cyclin D1, cyclin A, cyclin-dependent kinase (CDK)4, CDK2, hypoxia-inducible factor 1, vascular endothelial growth factor, CD31 (platelet endothelial cell adhesion molecule-1) and LYVE-1 (lymphatic vessel endothelial receptor 1) was significantly decreased in the mice received 20 mg/kg piceatannol as compared to mice received vehicle. Piceatannol significantly increased the numbers of TUNEL-positive, apoptotic cells in tumor tissues, which was accompanied by increased Bax and cleaved caspase-3 expression and reduced Bcl-2 expression. Additionally, piceatannol feeding reduced the number and volume of pulmonary tumor nodules, which was accompanied by reduced expression of matrix metalloproteinase-9 in lung tissues. Piceatannol induced a significant reduction in the blood levels of chemokine ligand (CXCL) 16, CXCL13 (BCA-1), interleukin-16, macrophage colony-stimulating factor, monocyte chemoattractant protein-1, triggering receptor expressed on myeloid cells-1, stromal cell-derived factor-1, and plasminogen activator inhibitor-1 compared to the vehicle-fed mice. The present results indicate that piceatannol has an ability to inhibit breast cancer development and metastasis and this effect is attributable to its ability to inhibit tumor angiogenesis, lymphangiogenesis and reduce the blood levels of a broad variety of cytokines and chemokines.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 606. doi:1538-7445.AM2012-606
Abstract 610: The role of oxidative stress in the growth inhibitory and proapoptotic effects of brown button mushrooms (Agaricus bisporus) in human prostate cancer cells
Authors: Xu Tongtong , Beelman Robert , Lambert Joshua
Published: August 2012

An increasing body of clinical and in vivo/in vitro studies suggests that some chemical components in specialty mushrooms like maitake (Grifola frondosa) may exert cancer preventive effects. Edible mushrooms, which have a similar content of polysaccharides, proteoglycans, steroids, etc., have been less well-studied for their anticancer and cancer preventive activity. For example, only one publication has reported the inhibition of human breast cancer cell growth by brown button mushrooms (Agaricus bisporus). The objectives of our research were to evaluate the anti-prostate cancer activity and mechanism(s) of action of brown button mushroom extracts. A hot water extract was prepared from freeze-dried brown button mushroom powder and fractioned with hexane and ethyl acetate. The IC50 of ethyl acetate fraction from brown button mushrooms (BBEA) was ∼0.1mg/ml. The inhibitory potency against LNCaP human prostate cancer cells correlated with the total phenol content, suggesting that these may be the active anticancer components. To further investigate the mechanisms of BBEA's anticancer effects, we examined the production of H2O2 by the extract using FOX assay and examined oxidative stress, proapoptotic, and cell cycle arrest markers by western blot. BBEA (0.1mg/ml) produced ∼50µM H2O2 under cell culture conditions after 6h. The expression of the oxidative stress marker, αH2A.X, in LNCaP cells was enhanced by BBEA after 12 and 24h, suggesting that pro-oxidative effects may be a possible anticancer mechanism. BBEA also increased caspase-3 and PARP cleavage and reduced the expression of Cyclin D1 and Cyclin E2, suggesting induction of apoptosis and cell cycle arrest by BBEA. In summary, this is the first report of the anticancer effects of phenolic compounds in brown button mushrooms and these results demonstrate that further study of BBEA is warranted. Microarray studies are currently under way to better characterize the anticancer activity of BBEA against human prostate cancer cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 610. doi:1538-7445.AM2012-610
Abstract 614: Increased oxidative DNA damage in human prostate cancer and its relationship to GSTP1 expression
Authors: Kanwal Rajnee , Fu Pingfu , Gupta Sanjay
Published: August 2012

The pi-class glutathione S-transferase (GSTP1) has been described as a ‘caretaker’ gene, as it actively protects the cell from oxidative genome damage mediated by carcinogens and electrophilic compounds. Loss of GSTP1 expression via promoter hypermethylation is one of the most common epigenetic alterations observed in human prostate cancer. Silencing of GSTP1 can increase prostate epithelial cells more vulnerable to both oxidant and electrophile carcinogens and causes genetic aberrations leading to increased risk of tumor progression. Observations suggest that increased reactive oxygen species (ROS) causes DNA damage in cells, as measured by 8-hydroxy-2′-deoxyguanosine (8-OHdG), contribute to increased incidence of prostate cancer. However there are no studies which demonstrate correlation between GSTP1 protein/activity and DNA damage in prostate cancer. We took a panel of 24 human prostate specimens obtained after surgery which comprised of matched primary tumor and adjacent nontumorous (benign) prostate tissues. Oxidative DNA damage, GSTP1 protein expression and its activity, and GSTP1 promoter methylation was assessed. The 8-OHdG levels in DNA of prostate cancer tissues ranged from 0.307 to 0.609ng/μg DNA, whereas the levels in benign tissue range from 0.156 to 0.322ng/μg DNA, respectively. 8-OHdG and GSTP1 promoter methylation levels were higher in adenocarcinoma compared to their benign counterparts, which positively correlated with the loss of GSTP1 activity. The GSTP1 protein activity of prostate cancer tissues ranged from 738.2 to 1754.4ng/mg protein, whereas the levels in benign tissue range from 1728.6 to 2580.4ng/mg protein. The loss of GSTP1 expression in cells might increase their vulnerability to cytotoxicity and reactive oxygen species (ROS)-mediated DNA damage. In further experiments, human prostate carcinoma LNCaP cells, which contains a silenced GSTP1 gene, was genetically modified to constitutively express high levels of GSTP1. Introduction of GSTP1 lowered endogenous ROS levels in LNCaP cells; treatment with H2O2 significantly reduced ROS and 8-OHdG in LNCaP-GSTP1 cells, compared to parental cell line. Furthermore, treatment with green tea polyphenols to LNCaP cells caused re-expression of GSTP1 which protected the cells from H2O2-mediated DNA damage compared to pretreated cells. These results suggest that oxidative stress-induced DNA damage may be an important measure for primary prevention of prostate cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 614. doi:1538-7445.AM2012-614
Abstract 620: Chemoprevention of hydroxybutyl(butyl)nitrosamine (OH-BBN)-induced mouse urinary bladder cancer by the kava chalcone flavokawain A
Authors: Xu Xia , Liu Zhongbo , Liu Shuman , Li Xuesen , Zi Xiaolin
Published: August 2012

About 75% of human bladder cancers are associated with cigarette smoking or exposure to industrial carcinogens. Kava roots have been traditionally used to prepare beverage and herb medicine in the South Pacific Island nations (Fiji, Vanutu, Samoa, etc.) for thousands of years. Recently, an epidemiological study has linked high kava consumption to lower incidences of cancers, including lung and bladder cancers, despite the presence of many smokers in the populations of the South Pacific Islands. We therefore examined the potential of flavokawain A, a predominant chalcone isolated from the kava plant for prevention of mouse urinary bladder cancer induced by the organ-specific and tobacco-smoking related nitrosamine OH-BBN. B6D2F1 mice at 8 weeks of age were gavaged 7.5 mg OH-BBN once per week for 12 weeks. In the standard prevention protocol, 0.1% FKA or vehicle food was administered as a dietary supplement to each group of mice beginning 1 week before the first OH-BBN administration and ending 32 weeks after the initial OH-BBN treatment. Dietary feeding of OH-BBN treated mice with 0.1% flavokawain A in the mouse diet decreased bladder wet weight by about 57% (Bladder weights for control versus flavokawain A were 74.18 ± 16.7 versus 32 ± 1.5 mg; P<0.01). In the standard promotion protocol, 0.1% FKA or vehicle food was given 1 week after the final OH-BBN administration for 19 weeks. Flavokawain A also significant reduced the bladder wet weight by about 27% (Bladder weights for control versus flavokawain A were 89.4 ± 23.4 versus 65.5 ± 10.6 mg; p<0.05). To increase the incidence of palpable OH-BBN induced bladder tumors, we extended 7.5mg OH-BBN treatment once per week for one more week up to a total of 13 weeks. In this modified promotion protocol, the percentage of palpable tumors in control group has reached to about 53%, which is similar to that reported by published literatures. Dietary feeding of 0.6% flavokawain A significantly decrease bladder wet weight by 73% (Bladder weights for control versus flavokawain A were 314.9 ± 106.7 versus 87.3 ± 15.2 mg, p=0.0265). In addition, we showed that flavokawain A induced activities of phase II enzyme (i.e. glutathione S-transferase and quinone reductase) in different organs (bladder, liver, prostate, etc.) of mice. Taken together, these results suggest that flavokawain A deserves further investigation for bladder cancer chemoprevention by targeting smoking or carcinogens exposed populations.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 620. doi:1538-7445.AM2012-620
Abstract 621: The importance of antioxidant, antiangiogenesis and immune stimulation in cancer
Authors: Thornthwaite Jerry T. , Respess Henry , Shah Hare , Peeples William , Thornthwaite Kyle , Thornthwaite Bonita , Kent Patrick , Allen Mark
Published: August 2012

In our quest over the last nine years to find comprehensive over-the- counter supplements, designed to facilitate current classical treatments in fighting diseases, include antiangiogenic, immune and antioxidant defense systems. These supplements include, in part, Acetyl L-Carnitine (ALC), Alpha Lipoic Acid (ALA), Coenzyme Q10 (CoQ10), Curcumin with Piperine, Genistein, Lentinan, N-AcetylCysteine (NAC), Resveratrol, selenium, Vitamin B Complex, Vitamin C, Vitamin E and zinc. These ingredients have been demonstrated, either individually or collectively, to have antioxidant, anti-angiogenesis, and immune stimulation and antioxidant properties. Furthermore, the scientific literature supports direct cancer cell cytotoxicity for Curcumin, Geinstein and NAC. The dietary supplement activities are supported by over 50,000 references in the scientific literature (PubMed.com) and over 150 clinical trials (clinicaltrials.gov), not including the human-cancer publications (23,000) and clinical trials (2,100) with zinc and the vitamins. From the literature there is evidence that some of the antiangiogenesis components that affect the majority if not all pathways of angiogenesis, such as Curcumin, Genistein and NAC, actually stimulate the in vivo production of natural antiangiogenic compounds that include Angiostatin, Endostatin and Thrombospotin 1. All of the components play a role in serving as either water or lipid soluble (able to cross the blood-brain barrier) antioxidants. Curcumin, Genistein, Resveratrol, Lentinen, NAC, zinc, selenium and the B and C vitamins all stimulate the immune system. Except for ALC and CoQ10, the other components show anti-inflammatory activity. ALC, Resveratrol along with the B and C vitamins are helpful in treating fatigue. The components that help protect the brain and promote nerve regeneration include ALA, CoQ10, Resveratrol, NAC, selenium, zinc and the B/C vitamins. In conclusion, effective prevention and treatment from and for diseases such as cancer, heart disease and immune deficiency will require multiple compounds.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 621. doi:1538-7445.AM2012-621
Abstract 646: Soy food intake and risk of lung cancer: Evidence from the Shanghai Women's Health Study and a meta-analysis
Authors: Yang Gong , Shu Xiao-Ou , Chow Wong-Ho , Zhang Xianglan , Li Hong-Lan , Ji Bu-Tian , Cai Hui , Wu Sheng-Hui , Gao Yu-Tang , Zheng Wei
Published: August 2012

Background: Recent large-scale clinical trials raised concerns regarding increased risk of aggressive lung cancer and lung cancer mortality among users of postmenopausal estrogen therapy. Soy and its phytoestrogens have been shown to act as a natural estrogen antagonist and have cancer-inhibitory activities in experimental studies. Objective: We prospectively evaluated the association of soy food intake with lung cancer risk, overall and by tumor aggressiveness, and perform a meta-analysis of published data. Methods: Included in this analysis were 71,550 women recruited in the Shanghai Women's Health Study, a population-based cohort study. Usual soy food intake was assessed at baseline and re-assessed during follow-up through in-person interviews. Previous studies were identified through a MEDLINE search. Results: During a mean follow-up of 9.1 years, 370 incident lung cancer cases were identified; 340 were lifetime never smokers. After adjustment for potential confounders, soy food intake was inversely associated with subsequent risk of lung cancer; the hazard ratio (HR) for the highest compared with lowest quintile of intake was 0.63 (95% CI: 0.44 - 0.90; P trend = 0.004). This inverse association appeared predominately among women with a later age at menopause (P interaction = 0.01) and varied by tumor aggressiveness as defined by length of survival (<12 versus β12 months), with corresponding HR of 0.49 for more aggressive lung cancer versus 0.76 for less aggressive lung cancer (P heterogeneity = 0.057). Similar inverse associations were observed for isoflavone intake. A meta-analysis of seven studies conducted among never smokers found a summary odds ratio of 0.59 (95% CI: 0.49 - 0.71) for the highest versus lowest categories of soy or isoflavone intake. Conclusion: This study suggests that soy food consumption may reduce lung cancer risk in nonsmoking women, particularly for aggressive lung cancer, and its effect may be modified by endogenous estrogens.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 646. doi:1538-7445.AM2012-646
Abstract 656: Clinical profiles predict early non-adherence to adjuvant endocrine treatment in a prospective breast cancer cohort
Authors: Markkula Andrea , Hietala Maria , Henningson Maria , Ingvar Christian , Rose Carsten , Jernström Helena C.
Published: August 2012

Non-adherence to adjuvant endocrine breast cancer treatment adversely affects disease-free and overall survival. Clinical predictors of non-adherence may allow for specific interventions to reduce non-adherence and improve survival. The aim was to investigate whether clinical characteristics predict non-adherence. Clinical characteristics and information on adherence were obtained from 417 breast cancer patients in a population-based prospective cohort from southern Sweden using patient charts, pathology reports, and questionnaires filled out at the 1- and 2-year follow-up visits. A BMI<25, preoperative current smoking, and drinking alcohol less often than twice a month predicted non-adherence at the 1-year (OR 6.43, 3.12-13.24) and the 2-year visits (OR 4.91, 2.33-10.36) in patients with at least two of these clinical characteristics. When low histological grade (I) was added to the model, having at least two of these four clinical characteristics predicted non-adherence at the 1-year (OR 5.84, 2.73-12.51) and the 2-year visits (OR 5.66, 2.54-12.63) and identified >72% of the non-adherent patients. Thirteen non-adherent patients declined treatment and were never prescribed endocrine treatment. In conclusion, two clinical profiles predicted early non-adherence and may be clinically useful if validated in an independent cohort.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 656. doi:1538-7445.AM2012-656
Abstract 657: Perinatal factors and breast cancer risk: The CECILE study
Authors: Menegaux Florence , Anger Antoinette , Truong Therese , Guenel Pascal
Published: August 2012

Objectives: Perinatal period and adolescence are key periods of breast cancer development with increased susceptibility to carcinogens. A high level of endogenous estrogens in utero was suggested as a possible risk factor for breast cancer in daughters. We investigated the role of perinatal factors in breast cancer in the CECILE study, a population-based case-control study. Methods: The CECILE study was conducted in two French départements (Côte d'Or, Ille-et-Vilaine) between 2005 and 2008. A total of 1232 incident breast cancer cases and 1317 population age-matched controls were included. An in-person interview was conducted using a standardized questionnaire to obtain information on recognized or suspected risk factors for breast cancer. A self-administered questionnaire was used to obtain information on perinatal factors and was returned by mail by 871 cases (71%) and 915 controls (69%). The perinatal questionnaire included information on parental characteristics (maternal and paternal age, maternal smoking status, hypertension or pre-eclampsia during pregnancy, exposure to diethylstilboestrol) and women’ birth characteristics (birth weight, length at birth, preterm birth, birth order and having been breast-fed). Analyses were conducted using unconditional logistic regression adjusting for age and recognized risk factors for breast cancer. Results: With the exception of maternal smoking (OR=0.57 [0.38-0.85]), there was no association between breast cancer risk and the other parental characteristics. We observed a J-shaped association between birth weight and breast cancer risk, with an OR of 1.54 [1.15-2.06] in women whose birth weight was 3500 grams or more as compared with women whose birth weight was 2500 to 3499 grams. We also observed an increased risk of breast cancer with an increase of birth order (OR=1.12 [0.91-1.37] for birth order 2 to 4; OR=1.42 [1.02-1.99] for birth order [[Unsupported Character - [[Unsupported Character - ]]]] 5, p trend=0.04). No association were observed for women who have been breast-fed, for length at birth or preterm birth. Conclusion: Our results support the hypothesized association between intrauterine estrogens exposure and risk of breast cancer in daughters.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 657. doi:1538-7445.AM2012-657
Abstract 66: Inhibition of glioma cell proliferation and tumor development by Sox21
Authors: Caglayan Demet , Kastemar Marianne , Westermark Bengt , Ferletta Maria
Published: August 2012

Sox2 and Sox21 are two transcription factors important for the developing, as well as the adult, CNS, and they are often co-expressed. Sox2 is an embryonic stem cell marker, whereas ectopic forced expression of Sox21 has been shown to induce differentiation in embryonic stem cells. Further, Sox2 is important for maintenance of neural stem cells whereas Sox21 is important for neurogenesis. These two transcriptionfactors are thus in opposite relation to each other and it is believed that a proper balance between them is needed to regulate target genes. Sox2 is highly expressed in brain tumors and up to 97% of GBM samples express Sox2. While the expression of Sox2 has been shown in GBM, in primary glioma cells and established glioma cell lines, less is known about Sox21 in glioma. We have previously shown that Sox2 and Sox21 are co-expressed in adult and childhood brain tumors and are in a functional relationship in glioma cells. Sox2 keeps glioma cells in a proliferative state whereas over expression of Sox21 reduces Sox2 expression and decreases cell proliferation with an increased tendency of apoptosis and differentiation of the glioma cells. We have now further elucidated this effect in vivo by injecting established inducible-Sox21 glioma cell lines subcutaneously into the flank and orthotopically into the brain of SCID mice. Regardless of the injection site, increased Sox21 expression in these tumors reduces tumor growth. The tumors from treated mice were significantly smaller in size and there is a significant increase in survival time. This effect was dependent on the time of Sox21 induction, where an earlier turn on gives even smaller tumors. Total depletion of Sox2 was not achieved despite forced Sox21 expression. Further we show that Sox2 deficiency leads to an inability to form tumors. With its dual effect, the ability to decrease Sox2 expression and the ability to aberrantly differentiate tumor cells, Sox21 becomes a very important factor for future research around therapeutic possibilities in GBM.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 66. doi:1538-7445.AM2012-66
Abstract 664: Menthol cigarettes in relation to breast cancer incidence in African American women
Authors: Bethea Traci N. , Rosenberg Lynn , Boggs Deborah A. , Palmer Julie R.
Published: August 2012

The Tobacco Products Scientific Advisory Committee has found that smokers of menthol cigarettes have an earlier age at smoking initiation, less success in smoking cessation, and are more likely to be African American than smokers of non-menthol cigarettes. However, whether menthol cigarettes are associated with higher cancer risk relative to non-menthol cigarettes is unclear. Recent studies of smoking and breast cancer suggest that long-term smoking may associated with a small increase in risk, but no data are available on type of cigarette. We assessed the relative effects of menthol and non-menthol cigarettes on incidence of breast cancer in a large prospective cohort of African American women. The Black Women's Health Study has followed approximately 59,000 women with biennial questionnaires since enrollment in 1995. Beginning in 2003, data has been collected on whether cigarettes smoked were menthol or non-menthol; menthol cigarettes were reported by 64.7% of smokers who provided information. During follow-up from 2003 through 2010, 739 incident breast cancer cases occurred. In proportional hazard models that controlled for age and numerous breast cancer risk factors, hazard ratios (HR) were computed for categories of pack-years of smoking of the two types of cigarettes relative to a reference group of never-smokers who reported no regular exposure to second-hand smoke. The HR for β20 pack-years of smoking non-menthol cigarettes was 1.70 (95% confidence interval (CI) 1.04-2.76); for β20 pack-years of smoking menthol cigarettes, the HR was 1.14 (95% CI, 0.72-1.82). Our findings suggest that, to the extent that higher pack-years of smoking may be associated with breast cancer, smoking menthol cigarettes is not more harmful than smoking non-menthol cigarettes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 664. doi:1538-7445.AM2012-664
Abstract 673: Obesity, weight gain, physical activity and polymorphism in mTOR pathway and risk of renal cell carcinoma
Authors: Shu Xiang , Lin Jie , Wood Christopher G. , Tannir Nizar M. , Wu Xifeng
Published: August 2012

Background: The role of obesity, physical activity and weight gain in renal cell carcinoma (RCC) has not been well understood. Given the crucial role of PI3K-AKT-mTOR pathway (or mTOR pathway) plays in metabolism, cell growth and tumorigenesis, it is important to evaluate the joint effect of genetic variants in this pathway and energy balance risk factors for RCC. Methods: In this case-control study, 577 Caucasian cases and 593 Caucasian healthy controls were included in the analyses. Cases and controls were frequency-matched by age (±5 years), gender and county of residence. Epidemiological data were collected via in-person interview. Genotyping data of 157 SNPs was extracted from previous GWAS which has been done using Illumina HumanHap660K/610K BeadChips in the laboratory. Unconditional logistic regression was used to calculate odds ratios and their 95% confidence interval (CI). Results: Obesity at age 20, age 40 and 3 years prior to the diagnosis or recruitment were each significantly associated with increased RCC risk. Moderate (10.1-25 lbs) and massive weight gains (>25 lbs) from age 20 to 40 increased RCC risk by 46% (95%CI: 1.16-2.34) and 62% (95%CI: 1.10-2.39), respectively. Low physical activity was associated with 4.08-fold (95%CI: 2.92-5.70) of increased RCC risk. Three SNPs had significant association and their cumulative effect had increased the risk up to 85% (OR: 1.85, 95%CI: 1.28-2.68). When considering multiple risk factors, subjects who were overweight or obese, experienced weight gain during adulthood (>10 lbs), had history of hypertension and unfavorable genotypes in mTOR pathway had 12.84-fold increased risk (95%CI: 5.08-32.46) of RCC. Conclusion: Our results provided strong evidence that energy balance risk factors and genetic variants in mTOR pathway could jointly influence the susceptibility to RCC. Our findings have implications on RCC prevention if confirmed in future independent studies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 673. doi:1538-7445.AM2012-673
Abstract 695: Significant loss of nuclear expression of Actinin-4 in metastatic breast carcinoma and lymph nodes: A novel biomarker for metastatic breast carcinoma
Authors: Chen Cui P. , Herrmann Marille , Akoa Achille , Alper Özgül M. , Alper Özge
Published: August 2012

Background: Actinin-4 is an actin cross-linked protein. The expression and subcellular distribution of actinin-4 (ACTN4) has been associated with multiple roles in tumorigenicity and cancer metastasis. In the present study, we developed a novel antibody against human actinin-4 and investigated the clinical utility of actinin-4 as a biomarker in metastatic breast cancer. Methods and findings: We generated a novel monoclonal antibody (AB-Actinin-4) using hybridoma technology and native ACTN4 protein as an immunogen. The antibody specifically recognized both native and denatured human Actinin-4 protein and displayed high affinity as assessed by ELISA, immunohistochemistry assay, western blot and flow cytometry. Using this antibody and ELISA as well as immunohistochemical techniques, we examined plasma levels and tissue expression of actinin-4 in healthy controls’ and breast cancer patients’ samples. 50 plasma samples from healthy controls and breast cancer patients were analyzed for the presence of soluble actinin-4. ELISA results showed significantly decreased actinin-4 levels in plasma samples from patients with breast carcinomas compared to healthy control plasma. A total of 156 cases, including 70 normal, 36 non-metastatic breast carcinoma, 50 breast carcinoma tissues with regional metastasis, and 50 matched metastatic lymph nodes were examined. The immunoreactivity of actinin-4 was located mainly in nucleus and cytoplasm of cells. To assess the difference between groups, the staining intensity and intracellular distribution were compared and the intensity in nucleus and cytoplasm was separately scored as 0, 1+, 2+ and 3+. Grades 0 and 1+ were defined as negative and 2+ and 3+ as positive. Significant differences between the groups were found in nuclear staining. 92% of normal and 89% of non-metastatic breast carcinoma samples displayed positive nuclear staining. In contrast, only 29% of metastatic lymph nodes and 51% of metastatic breast cancer tissues showed strong nuclear staining. Conclusion: Actinin-4 demonstrated significantly decreased expression in plasma from breast cancer patients. Metastasis leads to significant loss of the nuclear expression of Actinin-4 in breast cancer tissues, in comparison to normal and non-metastatic breast carcinoma tissues. Our data suggests that Actinin-4 might have significant impact in breast cancer metastasis. Actinin-4 may serve as a reliable biomarker for the diagnosis and prognosis of metastatic breast cancer as well as could be a therapeutic target.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 695. doi:1538-7445.AM2012-695
Abstract 697: Clinical and prognostic comparison between triple-negative and non-triple-negative breast cancer
Authors: Ding Shian-Ling , Lee I , Cheng Chun-Wen , Lin Yu Hsin , Chang Jia-Ming , Shen Chen-Yang
Published: August 2012

Aim: The triple-negative breast cancer (TNBC) subtype is characterized by the lack of expression of estrogen and progesterone receptors (ER/PR) and Her2/neu protein. The present study aimed to evaluate the five-year survival rates and clinico-pathological characteristics of patients with TNBCs and those with non-TNBCs in Taiwan. Methods: This study was conducted on 313 ethnic Chinese women with primary breast cancer using tissue microarrays to perform a standardized immunohistochemical analysis. Results: Of the 313 patients, 10.5% had the TNBC phenotype. The median age of the TNBC patients was lower than that of the non-TNBC patients (47 vs. 59 years). One of the more striking differences between the TNBC and non-TNBC women was tumor differentiation, with 29.6% of the non-TNBC group having a poorly differentiated tumor compared to 45.5% of the TNBC group (p=0.01). Cox proportional hazards model results showed that (a) ER, PR, or Her2/neu status was not associated with survival rate in early-stage patients and (b) ER negativity (p = 0.03, HR = 3.4) and Her2/neu negativity (p = 0.04, HR= 4.4) were two independent predictors of the five-year survival rate in advanced-stage (stage III-IV) women. Conclusion: The TNBC phenotype represents a specific molecular profile. However, it does not always lead to worse survival, especially in women with early breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 697. doi:1538-7445.AM2012-697
Abstract 707: CD133 is a useful surrogate marker to predict chemosensitivity of neoadjuvant chemotherapy for breast cancer
Authors: Aomatsu Naoki , Yashiro Masakazu , Kashiwagi Shinichiro , Morisaki Tamami , Fukuoka Tatsunari , Hirakawa Tosiki , Hasegawa Tsuyoshi , Matsuoka Junko , Takashima Tsutomu , Kawajiri Hidemi , Onoda Naoyoshi , Ishikawa Tetsuro , Hirakawa Kosei
Published: August 2012

Background:Current studies have demonstrated that neoadjuvant chemotherapy (NAC) improves survival outcomes and increases the chance for breast conservation when applied preoperatively. However, no reliable maker to predict chemosensitivity of NAC is not available. CD133 has been considered as a cancer stem cells (CSCs) marker in many kinds of tumors such as breast cancer, colorectal cancer and brain cancer. The aim of this study was to evaluate the value of CD133 as a surrogate maker to predict chemosensitivity of NAC for breast cancer. Experimental Design: A total of 102 patients with breast cancer of stage II and III, as evaluated by core needle biopsy and ultrasonography, was treated with NAC. Expressions of CD133, estrogen receptor, progesterone receptor, and HER2 were assessed by immunohistochemistry. Results: The clinical complete response (CR) rate of all patients was 18% (18/102), partial response (PR) was 61% (62/102), no change (NC) was 20% (20/102), and progressive disease (PD) was 2% (2 /102). The response rate (RR) was 78% (80/102). The pathological complete response rate (pCR) was 29%. The pCR rate and pathological response of CD133-positive cases was significantly lower than that of CD133-negative cases. The recurrence rate of CD133-positive cases was significantly higher than that of CD133-negative cases. CD133 expression showed a poor disease free survival and overall survival time. A multivariate logistic regression analysis showed that CD133 expression was an independent prognostic factor in breast cancers treated with NAC. Conclusion: CD133 is a useful surrogate maker to predict chemosensitivity of NAC chemotherapy for breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 707. doi:1538-7445.AM2012-707
Abstract 71: Mutational analysis for IDH1 and IDH2 in pediatric leukemia
Authors: Hiwatari Mitsuteru , Takita Junko , Nishimura Riki , Okubo Jun , Oki Kentaro , Sanada Masashi , Sotomatsu Manabu , Kikuchi Akira , Igarashi Takashi , Hayashi Yasuhide , Ogawa Seishi
Published: August 2012

Recently, mutational and epigenetic profiling of a large acute myeloid leukemia (AML) patient cohort revealed that NADP+dependent isocitrate dehydrogenase (IDH)1/2-mutated AMLs display global DNA hypermethylation and a specific hypermethylation signature, suggesting a shared proleukemogenic effect. To explore the involvements of IDH1/2 in the pathogenesis in pediatric hematological malignancies. We analyzed mutations that involve the activation sites of IDH1/2 using polymerase chain reaction amplification/sequencing in a total of 244 samples of pediatric myeloid malignancies as well as infantile leukemia including 17 AML-derived cell lines, 115 primary cases of AML, 28 primary cases of MDS, 15 primary cases of juvenile myelomonocytic leukaemia (JMML), 6 chronic myeloid leukemia (CML)-derived cell line, 18 primary cases of CML and 45 infantile leukemia(6 AML and 39 acute lymphoblastic leukemia (ALL) patients). Moreover, to assess whetherIDH1/2 mutations overlap with known gene abnormalities, such as FLT3, c-KIT, and NPM1 mutations, mutational analyses of FLT3, c-KIT, and NPM1 were also performed. The common IDH2 R140Q mutation was detected in a single AML case, whereas no IDH1 mutation was detected in samples of myeloid malignancies. Although no IDH2 mutation was detected in infantile leukemias, novel P127S, H133I and I130V of IDH1 mutations were detected in 4 of 45 (8.9%) infantile ALL cases. No IDH1 and IDH2 mutations were detected in the JMML, MDS, or CML samples examined. Six AML samples including one cell line had c-KIT mutations (D816V, N822K, or D419fs), 12 AML cases had FLT3-ITD and 10 infantile leukemia cases had FLT3 mutations (D835E or I836). The NPM1 mutation was detected in 2 of 132 AML samples. The AML case harboring the IDH2 mutation, Case 39 was a 12-year-old boy diagnosed as AML-M2 according to the French-American-British cooperative group classification system having t(8;21)(q22;q22), showed no abnormalities of NPM1, c-KIT, and FLT3. Remarkably, among 4 infantile ALL cases with IDH1 mutations, 3 cases showed mixed lineage leukemia(MLL) rearrangements with t(4;11). The FLT3-D835 mutation was found in 1 of 4 patients with IDH1 mutations. These results suggest that although the involvements of IDH1/2 mutations in the pathogenesis of pediatric myeloid malignancies are extremely rare, closely positioned to near activation site, R132 IDH1, these IDH1 mutations are the candidate second genetic events in a subset of MLL-leukemia.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 71. doi:1538-7445.AM2012-71