bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 83: Comparison of surface-directed and classic androgen receptor antagonists
Authors: Suh Ji Ho , Chattopadhyay Arundhati , Sieglaff Douglas H. , Storer Cheryl L. , Cox Marc B. , Webb Paul 
Published: August 2015

Abstract
Background: The androgen receptor (AR) surface-directed antagonist MJC13 inhibits AR function and proliferation of prostate cancer (PC) cells and these effects are related to arrest of an AR/chaperone complex in the cytoplasm. Here, we compared activities of MJC13 and the classic AR antagonist flutamide.
Method and Results: MJC13 and flutamide inhibit all dihydrotestosterone (DHT)-dependent genes in LNCaP PC cells and both compounds are equally effective. Control ChIP assays confirm that MJC13 inhibits AR binding to the prostate specific antigen (PSA) promoter more strongly than flutamide, consistent with different mechanisms of action. Examination of efficacy of MJC13 in conditions that reflect aspects of castrate resistant prostate cancer (CRPC) reveals that it inhibits a flutamide-dependent AR mutant (ART877A), but displays greatly restricted gene-specific activity in 22Rv1 cells that express a constitutively active truncated AR and is inactive against glucocorticoid receptor (GR), which can co-opt androgen-dependent signaling networks in CRPC. While flutamide inhibits AR interactions with the coactivator SRC2, it does not affect β-catenin binding. In contrast, MJC13 inhibits AR interactions with both coregulators and, unlike flutamide, strongly inhibits amplification of AR activity obtained with SRC2 and β-catenin. MJC13 also preferentially inhibits β-catenin-enhanced cell division in LNCaP cells relative to flutamide.
Conclusion: Our findings suggest that a surface-directed antagonist can block AR activity in some conditions in which a classic antagonist fails and may display utility in some forms of CRPC.
Citation Format: Ji Ho Suh, Arundhati Chattopadhyay, Douglas H. Sieglaff, Cheryl L. Storer, Marc B. Cox, Paul Webb. Comparison of surface-directed and classic androgen receptor antagonists. [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 83. doi:10.1158/1538-7445.AM2015-83
Abstract 85: CCAAT/enhancer binding protein beta facilitates castrate-resistant prostate cancer cell growth and sensitivity to mTOR inhibitors
Authors: Barakat David J. , Zhang Jing , Friedman Alan D. , Denmeade Samuel R. , Paz-Priel Ido 
Published: August 2015

Abstract
Adaptive changes that frequently occur in castrate-resistant prostate cancer (CRPC) cells are genomic mutations which enhance the activity of the PI3K-mTOR signaling pathway. Although there have been several promising clinical trials for the treatment of CRPC utilizing inhibitors of mTOR, these efforts failed to show significant improvement of patient outcomes. Thus, identifying potential mechanisms of resistance to these agents could improve their therapeutic efficacy. CCAAT/enhancer binding protein beta (C/EBPβ) is a broadly expressed transcription factor, with three isoforms that are differentially translated by mTOR activity. T reatment of cells with mTOR inhibitors increases the translation of the larger C/EBPβ LAP isoforms and decreases the truncated LIP isoform. The function of C/EBPβ LAP has been previously associated with survival and cellular senescence, while the LIP isoform facilitates cell cycle progression. Our central hypothesis was that the differential translation of LAP and LIP C/EBPβ isoforms was essential for the survival of CRPC cells treated with mTOR inhibitors. We found that treatment of PC3 cells with mTOR inhibitors unexpectedly increased the protein levels of all three C/EBPβ isoforms, while androgen-sensitive LNCaP cells largely showed decreased C/EBPβ protein levels. However, the PI3K inhibitor LY294002, decreased the LIP isoform of C/EBPβ without affecting LAP expression in LNCaP and PC3 cells. C/EBPβ gene expression decreased in both LNCaP and PC3 cells in response to treatment with mTOR inhibitors. We next evaluated whether C/EBPβ facilitated cell survival during mTOR inhibition. We found that PC3 cells deficient in C/EBPβ, via shRNA knockdown or TALEN gene editing, were less sensitive to the mTORC1/2 inhibitor, INK128, as assessed by a significant increase in IC50 value determined by the WST-1 assay. Further, suppression of C/EBPβ through shRNA KD or TALEN targeting dramatically decreased the rate of PC3 cell growth, clonogenic potential and induced a senescent phenotype. Intriguingly, loss of C/EBPβ in LNCaP cells increased clonogenic potential. Collectively, these data suggest that C/EBPβ has a differential role for cell growth in androgen-sensitive versus castrate-resistant prostate cancer and that C/EBPβ levels inversely correlate with mTOR inhibitor resistance.
Citation Format: David J. Barakat, Jing Zhang, Alan D. Friedman, Samuel R. Denmeade, Ido Paz-Priel. CCAAT/enhancer binding protein beta facilitates castrate-resistant prostate cancer cell growth and sensitivity to mTOR inhibitors. [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 85. doi:10.1158/1538-7445.AM2015-85
Abstract 855: History of oral contraceptive use in breast cancer patients and risk for early breast cancer events
Authors: Huzell Louise , Persson Mia , Simonsson Maria , Markkula Andrea , Ingvar Christian , Rose Carsten , Jernström Helena C. 
Published: August 2015

Abstract
Whether previous oral contraceptive (OC) use impacts on prognosis women who subsequently develops breast cancer is unclear. The aim was to study history of OC use in relation to breast cancer events in a prospective population-based cohort.
Between 2002 and 2011, primary breast cancer patients without preoperative treatment were enrolled in Lund, Sweden and followed until December 2012. Tumor characteristics, clinical data, and date of death were obtained from pathology reports, patient charts, and population registries. History of OC use was obtained from preoperative questionnaires.
Among the 948 patients with invasive cancer and no metastasis detected on the postoperative screen, 74% had ever used OCs. Patients were followed for up to nine years and 100 breast cancer events were recorded. Ever OC users had significantly smaller tumors than patients who never used OCs (Ptrend = 0.013). However, there was a significantly higher frequency of grade III tumors in patients with OCs use before age 20 (Ptrend = 0.013), compared to patients with later start or never use. Ever OC use was not associated with prognosis, irrespective of duration. However, any OC use before age 20 was associated with a 3-fold increased risk for breast cancer events in patients younger than 50 years at diagnosis (adjusted HR 3.26: 95% CI 1.06-10.01) adjusted for age, tumor size, axillary lymph node involvement, histological grade, estrogen receptor status, and body mass index, but not in patients 50 years or older at diagnosis (Pinteraction = 0.009). In conclusion, these findings warrant confirmation in an independent cohort. If confirmed, history of OC use may yield prognostic information in addition to currently used criteria.
Citation Format: Louise Huzell, Mia Persson, Maria Simonsson, Andrea Markkula, Christian Ingvar, Carsten Rose, Helena C. Jernström. History of oral contraceptive use in breast cancer patients and risk for early breast cancer events. [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 855. doi:10.1158/1538-7445.AM2015-855
Abstract 86: Live-cell profiling of inhibitors targeting the N/C interaction within the androgen receptor
Authors: Yurlova Larisa , Buchfellner Andrea , Gregor Jacqueline , Romer Tina , Hickson Ian 
Published: August 2015

Abstract
Androgen receptor (AR) is an important target for drug therapies combating prostate cancer. However, various acquired mutations within the AR sequence often render resistance to these treatments. Since intramolecular interactions between the N- and C-terminus of AR are implicated in AR activation, it is essential to understand how AR inhibitors alter the N/C interaction within the AR, both for the wt receptor and for its mutant forms.
In this study we applied our recently developed Fluorescent-Two Hybrid (F2H) assay for live-cell analysis of AR N/C interactions. F2H enables real-time visualization and quantitative analysis of interactions between GFP- and RFP- tagged proteins in live mammalian cells. The F2H principle employs a tethering strategy: a GFP-tagged protein is enriched at the protein interaction platform of engineered F2H-BHK cells and serves as bait, whereas an RFP-tagged protein serves as a prey. Here, AR-LBD (wt or mut) was fused to GFP, AR-TAD was fused to RFP, both constructs were co-transfected into the F2H cells, treated with modulatory compounds and the LBD/TAD interactions were evaluated by fluorescence microscopy.
With F2H we analyzed the effects of DHT +/- flutamide, abiraterone, bicalutamide and enzalutamide in live cells. As expected, we observed striking differences in the effects of these treatments on the interactions between the AR-TAD and wt or mut AR-LBD (wt vs W741L, F876L, T877A, F876L-T877A). Further, we compared the effects of the selected compounds on AR-TAD and AR-LBD (wt vs mut) interactions in dose-response F2H assays. We also compared kinetics of these inhibitors with real-time imaging in F2H cells. We further validated our F2H findings with cell-lysate-ELISA on GFP-multiTrap plates. The acquired results correlate well with the published proliferation/reporter-assay data and clarify the role of the intramolecular AR N/C interactions in downstream effects.
Taken together, our results demonstrate that the fully reversible cellular F2H assay enables side-by-side profiling of new inhibitors and activators of protein-protein interactions with respect to their intracellular activity, cell penetration and kinetics.
Citation Format: Larisa Yurlova, Andrea Buchfellner, Jacqueline Gregor, Tina Romer, Ian Hickson. Live-cell profiling of inhibitors targeting the N/C interaction within the androgen receptor. [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 86. doi:10.1158/1538-7445.AM2015-86
Abstract 879: Menopausal hormone therapy and risk of primary liver cancer in the UK Clinical Practice Research Datalink
Authors: McGlynn Katherine A. , Hagberg Katrina , Chen Jie , Jick Susan , Sahasrabuddhe Vikrant V. 
Published: August 2015

Abstract
Background: The incidence of primary liver cancer (PLC) is three to four times higher among males than females in almost all countries. The discrepancy in rates is particularly notable prior to menopause, suggesting that estrogen exposure may be associated with lower risk. The relationship of menopausal hormone therapy (MHT) use to risk of PLC among women, however, has not been extensively examined.
Methods: We conducted a nested case-control study among women in the U.K.'s Clinical Practice Research Datalink (CPRD). Women diagnosed with primary liver cancer (n = 339) between 1988 and 2011 were matched to controls at a 4:1 ratio on age, index year, general practice and length of history in the CPRD. Odds ratios (OR) and 95% confidence intervals (95%CI) for associations of MHT with PLC were estimated using conditional logistic regression. All models were conditioned on the matching factors and adjusted for body mass index, HBV, HCV, smoking, alcohol-related disorders, diabetes, rare metabolic disorders, history of a bilateral oophorectomy, and use of certain medications, including paracetamol, aspirin, anti-diabetes therapies, and statins.
Results: Use of MHT for 6 months or longer was associated with a significantly lower risk of PLC (OR = 0.60, 95%CI = 0.39-0.92). Examination by length of MHT use found that use between 6-30 months was associated with significantly reduced risk (OR = 0.47, 95%CI = 0.24-0.91), while use greater than 30 months did not attain statistical significance (OR = 0.68, 95%CI = 0.41-1.13). When MHT was stratified by formulation (estrogen-only vs estrogen/progesterone), estrogen-only use was associated with significantly lower risk of PLC (OR = 0.51, 95%CI = 0.26-0.97) while estrogen/progesterone use did not attain statistical significance (OR = 0.65, 95%CI = 0.39-1.08).
Conclusion: MHT use, in particular estrogen-only MHT use, may be associated with lower risk of PLC. These findings are consistent with rodent models which have reported suppression of both fatty liver and hepatocarcinogenesis with administration of estrogen. As the association in the current study was apparent among users of 6-30 months, even short-term use of estrogen-only MHT may reduce risk.
Citation Format: Katherine A. McGlynn, Katrina Hagberg, Jie Chen, Susan Jick, Vikrant V. Sahasrabuddhe. Menopausal hormone therapy and risk of primary liver cancer in the UK Clinical Practice Research Datalink. [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 879. doi:10.1158/1538-7445.AM2015-879
Abstract 884: Associations of intakes of magnesium and calcium and survival among women with breast cancer: Results from Western New York Exposures and Breast Cancer (WEB) Study
Authors: Tao Menghua , Dai Qi , Millen Amy E. , Nie Jing , Edge Stephen B. , Trevisan Maurizio , Shields Peter G. , Freudenheim Jo 
Published: August 2015

Abstract
Background: Magnesium (Mg) and calcium (Ca) antagonizes each other in (re)absorption, cell cycle regulation, inflammation, and many other physiologic activities. However, few studies have investigated the association between Mg and Ca intakes and breast cancer survival, and the interaction between Ca and Mg intake.
Method: In a cohort of 1,170 women with primary, incident, and histologically confirmed breast cancer from Western New York State, we examined the relationship between intakes of these two minerals and survival. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI).
Results: Mean follow-up time was 87.4 months after breast cancer diagnosis; there were 170 deaths identified. After adjustment for known prognostic factors, and intakes of energy, total vitamin D and total Ca, higher dietary intake of Mg was inversely associated with risk of all-cause mortality (HR = 0.50, 95% CI, 0.28-0.90 for highest vs. lowest tertile; p trend = 0.02). Likewise, a marginal association was found for total Mg intake from foods and supplements combined (HR = 0.58, 95% CI, 0.31-1.08; p trend = 0.09). The inverse association of higher total Mg intake with all-cause mortality was primarily presented among postmenopausal women and was stronger among women who had a high Ca:Mg intake ratio (&gt;2.59). There were no clear associations for prognosis with intake of Ca.
Conclusion: We found that Mg intake alone may improve overall survival following breast cancer, and the association may be stronger among those with high Ca:Mg intake ratio.
Citation Format: Menghua Tao, Qi Dai, Amy E. Millen, Jing Nie, Stephen B. Edge, Maurizio Trevisan, Peter G. Shields, Jo Freudenheim. Associations of intakes of magnesium and calcium and survival among women with breast cancer: Results from Western New York Exposures and Breast Cancer (WEB) 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 884. doi:10.1158/1538-7445.AM2015-884
Abstract 90: K63-linked JARID1B ubiquitination by TRAF6 contributes to aberrant elevation of JARID1B in prostate cancer
Authors: Lu Wenfu , Liu Shenji , Li Bo , Xie Yingqiu , Adhiambo Christine , Yang Qing , Ballard Billy R. , Nakayama Keiichi I. , Matusik Robert J. , Chen Zhenbang 
Published: August 2015

Abstract
Aberrant elevation of JARID1B and histone H3 Lys4 trimethylations (H3K4me3) is frequently observed in many diseases including prostate cancer (PCa), yet the mechanisms on the regulations of JARID1B and H3K4me3 through epigenetic modifications still remain poorly understood. In this study we performed immunohistochemistry staining, immunofluorescence imaging, immunoprecipitation, shRNA and Western blotting analysis in mouse embryonic fibroblasts (MEFs), mouse models, and cultured human prostate cancer cells. As a result, we discovered that SKP2 modulates JARID1B and H3K4me3 levels in vitro in PTEN null prostate cancer cells and in vivo in Pten/Trp53 mouse models. We demonstrated that levels of SKP2, JARID1B and H3K4me3 are strikingly elevated in vitro and in vivo when both PTEN and P53 are inactivated. Importantly, SKP2 inactivation resulted in a reduction of cell growth, cell migration and malignant transformation of Pten/Trp53 double null MEFs, and further restrained prostate tumorigenesis of Pten/Trp53 mutant mice. Mechanistically, JARID1B is ubiquitinated by E3 ligase TRAF6 through the K63-linkage in prostate cancer cells. Interestingly, SKP2 contributes to JARID1B ubiquitination machinery as a non-E3 ligase regulator by decreasing TRAF6-mediated ubiquitination of JARID1B. SKP2 deficiency resulted in an increase of JARID1B ubiquitination and in turn a reduction of H3K4me3, and induced senescence through JARID1B accumulation in nucleoli of PCa cells and prostate tumors of mice. Furthermore, we showed that the aberrant levels of SKP2, JARID1B, and H3K4me3 are associated with malignant features of castration-resistant prostate cancer (CRPC) in mice. Overall, our findings reveal a novel network of SKP2- JARID1B, and targeting SKP2 and JARID1B may be a potential strategy for PCa control.
Citation Format: Wenfu Lu, Shenji Liu, Bo Li, Yingqiu Xie, Christine Adhiambo, Qing Yang, Billy R. Ballard, Keiichi I. Nakayama, Robert J. Matusik, Zhenbang Chen. K63-linked JARID1B ubiquitination by TRAF6 contributes to aberrant elevation of JARID1B in prostate 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 90. doi:10.1158/1538-7445.AM2015-90
Abstract 908: Impact of microbial metabolites and resveratrol in prostate cancer progression and clearance
Authors: Stokes James , Mishra Manoj K. 
Published: August 2015

Abstract
Short-chain fatty acids (SCFAs) are the chemical by-products of microbial fermentation. Resistant carbohydrates, some starches, and foods generally rich in fiber are used as substrates for this process. SCFAs are known to activate key cellular receptors such as GPR43/FFA2, which mediate programmed cell death in different cancer cells. Resveratrol (RES) is a polyphenolic compound found in select vegetables and fruits and has been known for its versatility in preventing and reversing a number of diseases including some cancers. Much like SCFAs, RES has the ability to induce programmed cell death in many clinical cancer models. To find out if the SCFAs and RES modulates the different pathways that controls the cancer progression, we utilized prostate cancer (PCa) cell lines to establish a) if, there is any homology between SCFAs produced by normal host epithelial cells and SCFAs produced by host intestinal microflora, and b) assess the in vitro/vivo effectiveness of derived SCFAs utilizing transgenic adenocarcinoma mouse prostate (TRAMP C1, C2, and C3) cell line(s), human prostate cancer cell line (PC-3) and live murine specimens, respectively. Preliminary data indicates that SCFAs and RES together regulate cell death pathways of PCa cells. Additionally, the SCFAs have the capability to manipulate different molecular signatures that directly govern the progression of PCa cells. Therefore, our data suggests that these two compounds (SCFAs and RES) share related biological pathways facilitated by intestinal microflora that can be used to regulate prostate cancer progression and clearance.
Citation Format: James Stokes, Manoj K. Mishra. Impact of microbial metabolites and resveratrol in prostate cancer progression and clearance. [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 908. doi:10.1158/1538-7445.AM2015-908
Abstract 917: The modulatory effects of cancer preventive herbal saponins on gut microbiota and mucosal environment in ApcMin/+ mice
Authors: Chen Lei , Singh Manreet , Leung Frederick CC , Hsiao W.L. Wendy 
Published: August 2015

Abstract
Human gut harbors 100 trillion microbes that is intrinsically linked to individual's health and diseases, including cancer. Triterpenoid saponins are present in many plants and are major active components in medicinal plants. Gynostemma pentaphyllum (Gp) is consumed as herbal tea as well as herbal medicine and found to possess anti-cancer effects in ApcMin/+ mice in our study. Here, we would like to address whether Gp saponins (GpS) can affect the gut microbiota in the ApcMin/+ colorectal cancer mouse model, and whether the alteration would have cancer preventive implication.
Using ERIC-PCR and 16S pyrosequencing analysis, we revealed that GpS treatment altered the overall fecal microbiome. Interestingly, it appeared that GpS treatment enhanced the relatively abundance of the beneficial microbes while reduced the potential harmful sulfate- and sulfur-reducing bacteria lineage. The impact of GpS on the gut mucosal environment was also examined. We found GpS improved the gut barrier function by increasing the numbers of Paneth cells, goblet cells, up-regulating the expression of E-cadherin and down-regulating the expression of N-cadherin in the intestine. In addition, GpS down-regulated the protein expression of beta-catenin and the p-STAT3. Furthermore, higher levels of anti-inflammatory and tissue repair-related cytokines as well as arginase I, but lower level of iNOS expression were found in GpS-treated ApcMin/+ mice. Altogether, GpS might affect the host-microbe interactions by regulating the gut microbial ecosystem and modulating the intestinal mucosal environment, which might contribute to its cancer preventive effect observed in the ApcMin/+ mice.
This study was supported by Macau Science and Technology Development Fund 015/2014/A1 and Research Grants Council of Hong Kong under GRF260413 to WL Wendy Hsiao.
Citation Format: Lei Chen, Manreet Singh, Frederick CC Leung, W.L. Wendy Hsiao. The modulatory effects of cancer preventive herbal saponins on gut microbiota and mucosal environment in ApcMin/+ mice. [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 917. doi:10.1158/1538-7445.AM2015-917