bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 945: The identification of subgroups of obese women with differing endometrial/systemic estrogenic metabolism: Potential consequences in the development of endometrial cancer
Authors: Villavicencio Alejandra , Medina Elizabeth , Muñoz Yenny , Peñaloza Paulina , Gaete Fancy , Castro Francisco , Albornoz Catalina , Celis Miguel , Vargas Macarena , Owen Gareth 
Published: August 2012

Abstract
Background: Enhanced endometrial proliferation correlates obesity to type-I (estrogen-dependent) endometrial cancer (EC). However, not all obese women develop type-I EC. Our laboratory identified cycling obese women without type-I EC with differing endometrial proliferation levels: Obese High Proliferating (OHP) and Obese Low Proliferating (OLP). We propose that these differences are the result of impaired endometrial/systemic estrogenic metabolism. Objectives: To assess the endometrial activity and/or expression of estrogen metabolic enzymes, such as aromatase and sulfatase, and the endometrial/systemic level of 17β-estradiol (E2), estrone (E1), estrone sulfate (E1-S) in those subgroups of obese patients. Methodology: The endometrial tissue and blood samples were obtained from pre-menopausal women in the proliferative phase (without type-I EC) with body mass index (BMI) = 18-24.9 Kg/m2 (normal-weight, N, n=10), BMIβ 30 kg/m2 (obese, OHP, n=14; OLP, n=6) and from obese women with type-I EC (n=12). Endometrial aromatase activity was assessed by measuring the amount of 3H2O released from tritiated androstenedione (substrate), and aromatase expression was measured by immunohistochemistry. Sulfatase activity was assayed using [3H] E1-S (substrate) and the [3H] product was determined by liquid scintillation. Endometrial and serum E2, E1, E1-S levels were determined by radioimmunoassay. Results: OHP demonstrated increased endometrial activity (26%, P&lt;0.05) and expression (71.8%, P&lt;0.05) of aromatase, higher endometrial E2 (25%, P&lt;0.05) and E1-S (20%, P&lt;0.05) levels, increased circulating E2 (57.1%, P&lt;0.05) and E1-S (42.6%, P&lt;0.05) levels compared with OLP group. In addition, OHP did not differ from OLP in endometrial sulfatase activity and endometrial/circulating E1 levels. No differences were observed between OLP and normal-weight groups in relation to aromatase activity/expression, circulating levels of E2, E1, E1-S, and endometrial levels of E2. Interestingly, obese women with type-I EC possessed similar aromatase and sulfatase activity as OHP. Conclusions: These data suggest that the E2 produced in the endometrial tissue from OHP group could amplify the estrogenic action of estrogens delivered via the circulation and explain the higher endometrial proliferation observed in this group. Our data may help identify obese women more susceptible to develop type-I EC, allowing early intervention and a potential reduction in mortality. (FONDECYT 1110232).
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 945. doi:1538-7445.AM2012-945
Abstract 946: Discovery of a novel benzotriazole-type retinoid X receptor partial-agonist decreasing plasma glucose level in type-2 diabetes mellitus with decreased side effects
Authors: Kakuta Hiroki , Yakushiji Nobumasa , Ohsawa Fuminori , Yamada Shoya , Nakayama Mariko , Kawata Kohei , Ohta Yui , Fujiwara Chisa , Oohashi Toshitaka , Makishima Makoto , Tai Akihiro , Yasui Hiroyuki , Yoshikawa Yutaka 
Published: August 2012

Abstract
Insulin-independent hypoglycemic agents have attracted attention, because type 2 diabetes mellitus is reported to be associated with an increased risk of cancer due to mitogenic effect of insulin. Insulin-independent antihyperglycemic effect can be obtained by LXR activation. LXR functions as heterodimers with retinoid X receptors (RXRs). RXRs also work with PPARs, which are known as targets for improvement of insulin resistance. Since LXR/RXR and PPAR/RXR can be activated by RXR agonists alone, and we are interested in RXR agonists for new hyperglycemia agents. However, well-known RXR agonists (RXR full-agonists) show significant weight gain and triglyceride elevation. Since these side effects are caused by excess activation of RXR, we hypothesized that RXR partial-agonists might be effective to decrease plasma glucose level without these problems. As a result, CBt-PMN, which has a benzotriazole structure, was discovered as an RXR partial-agonist, and significantly decreases plasma glucose level in type 2 diabetes model mice without the side effects described above.
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 946. doi:1538-7445.AM2012-946
Abstract 947: Molecular mechanism of WBP-2 coactivation function in estrogen receptor transactivation
Authors: Buffa Laura , Nawaz Zafar 
Published: August 2012

Abstract
The link between breast cancer and Estrogen Receptor alpha (ERα) is well established. The ERα is a ligand-inducible transcription factor that, upon binding to the hormone estrogen, regulates the expression of a variety of genes mainly involved in cell proliferation. Coactivators are proteins recruited by the hormone-activated receptor, which enhance the ERα transactivation functions acting as chromatin remodeling enzymes or adaptors between ERα and the transcriptional machinery. Our laboratory has previously identified WBP-2 (WW-domain binding protein 2) as bona fide coactivator of ERα. However, the molecular mechanism underlying WBP-2 coactivation function is not clear yet. In this study we investigate the mechanism by which WBP-2 acts as a coactivators of ERα. Our data show that knockdown of WBP-2 protein is associated with reduced expression of the ERα target gene pS2. Conversely, over-expression of the same protein results in increased pS2 expression. In order to clarify the mechanism governing these outcomes, we performed chromatin immunoprecipitation (ChIP) assays under WBP-2 knockdown conditions. We demonstrate here that WBP-2 binds to the pS2 promoter, and its knockdown is associated with decreased recruitment of the phosphorylated form of RNA PolII (associated with active transcription). Under similar conditions, the histone acetyl transferase p300 also exhibits reduced recruitment to the same promoter. Accordingly, decreased recruitment of p300 correlates with decreased histone acetylation. Collectively, our data indicate that WBP-2 enhances ERα transactivation function by facilitating the recruitment of a histone modifier enzyme that favors a relaxed chromatin structure permissive of transcription.
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 947. doi:1538-7445.AM2012-947
Abstract 950: Orphan nuclear receptor DAX1 exhibits suppressive effect on prostate cancer cell growth
Authors: Jia Lin , Chan Franky Leung 
Published: August 2012

Abstract
The nuclear receptor superfamily comprises a large group of transcriptional factors involved broadly in many physiological functions including control of embryonic development and cellular homeostasis. In general, nuclear receptors can bind to specific DNA regulatory elements (REs) as homo- or heterodimers. DAX1 (Dosage sensitive sex reversal (DSS), adrenal hypoplasia congenita (AHC) critical region, on chromosome X, gene 1, NR0B1) is a unique ligand-independent orphan nuclear receptor, which lacks the conventional DNA-binding domain (DBD) and in some cases it functions as a coregulatory protein inhibiting the transcriptional activity of other nuclear receptors by forming heterodimers. Previous studies show that DAX1 may play an essential role in establishment and maintenance of the steroidogenic axis of development, maintenance of murine embryonic stem cell pluripotency and cancer development including ovarian, breast and endometrial cancers. A recent report identified the inverse correlation of immunoreactivity of DAX1 with Gleason score of prostate cancer. In a preliminary investigation of expression patterns of members of nuclear receptor superfamily in a panel of immortalized prostatic epithelial cell and prostate cancer cell lines by semi-quantitative and real-time PCR, we observed that DAX1 displayed a variable expression pattern with low or undetectable levels in most tested immortalized prostatic epithelial cell lines and prostate cancer cell lines (including the classical LNCaP and PC-3) but high levels in some prostate cancer cells (VCaP, DuCaP, RC-58T and DU145) and also an in vitro model of transformed immortalized human prostatic epithelial cells BPH-1CAFTD. In order to elucidate the possible functional roles of DAX1 in the prostate cancer cell growth regulation, we generated DAX1-stable expression clones in two prostate cancer cell lines, LNCaP and PC-3, which expressed low endogenous DAX1 levels, by retroviral transduction for in vitro growth characterization. Our results showed that overexpression of DAX1 in LNCaP and PC-3 cells suppressed their in vitro cell proliferation, single-cell colony formation and anchorage-independent growth capacity in soft agar. Moreover, luciferase reporter gene assay showed that DAX1 suppressed the ERRα-induced transactivation of VEGFA. Our results suggested that DAX1 might perform a suppressive growth regulatory role in prostate cancer cells. (Lin Jia is supported by a RGC Hong Kong-PhD Fellowship Scheme)
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 950. doi:1538-7445.AM2012-950
Abstract 961: Pathways of tumorigenesis promoted by the growth factor progranulin in SW-13 adrenocortical carcinoma cells
Authors: Zhang Yonghua , Ismail Amin , Bateman Andrew 
Published: August 2012

Abstract
Adrenocortical carcinomas are highly malignant cancers, with a very low 5 year survival rate. The SW-13 cell line originated from a stage IV adrenocortical carcinoma, but is only poorly tumorigenic in mice. It can, however, be made highly tumorigenic in vivo if it is engineered to express a limited number of growth factors including progranulin (PGRN, also called PCDGF, granulin epithelin precursor, or proepithelin) and secreted FGFs. This provides a model system to study the transition of an adrenocortical carcinoma from low to a high malignant potential. PGRN is a secreted glycoprotein growth factor that is over produced by many cancers including those of the breast, ovary, endometrium, prostate, bladder, and liver. It acts on cancer growth by increasing mitosis, decreasing apoptosis and stimulating invasion. In addition, PGRN has been implicated as a stimulator of tumor stroma growth in breast cancer. We examined the expression of PGRN in SW-13 cells at different stages of the cell cycle. Cells were synchronized using two independent agents, L-Mimosine and aphidicolin to arrest cell division. Washout of the drugs released the SW-13 cells into the cell cycles with slow (L-Mimosine) or rapid (aphidicolin) kinetics, and PGRN expression increased in parallel with the increased proportion of cells in active cell division. Depleting PGRN mRNA levels slowed reentry into the cell cycle following drug removal. Inhibition of MEK1/2, phosphatidylinositol-3 kinase (PI3K), protein kinase C (PKC) and phospholipase-C-α (PLCγ) impairs proliferation of SW-13 cells carrying only empty vector (SW-13V) with differential effects on mitosis and apoptosis. In cells with elevated PGRN, (SW-13P), the anti-proliferative effects of inhibiting MEK1/2, PI3K and PKC, but not PLCγ, are attenuated. Inhibition of the stress kinase p38 increases proliferation of SW-13V, but not SW-13P cells, suggesting that PGRN and p38 have opposing effects on proliferation. Inhibition of p38 enhances the phosphorylation of MEK1/2 in SW-13V cells, while inhibiting PKC decreases it, suggesting that PKC and p38 pathways interact with the PGRN-regulated MEK1/2 signaling cascade. Transcriptional profiling indicated that expression of PGRN modulated levels of proteins in the Wnt and Notch-signaling pathways. These results suggest that PGRN expression may be coordinated with the cell cycle, and, may promote tumorigenesis by intervening in several signaling pathways.
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 961. doi:1538-7445.AM2012-961
Abstract 963: Epigenetic silencing of cancer-specific methylation may converge on therapeutic targets on human cancers
Authors: Yamashita Keishi , Kim Myoung Sook , Ooki Akira , Kato Hiroshi , Waraya Mina , Kawamata Hiroshi , Watanabe Masahiko , Sidransky David 
Published: August 2012

Abstract
(Background) We have identified numerous candidate tumor suppressor genes (TSGs) which are inactivated by cancer-specific CpG island methylation. We reviewed differential patterns of cancer-specific methylation in esophageal squamous cell carcinoma, gastric adenocarcinoma, and colorectal adenocarcinoma. (Matherials and Methods) A modified pharmacological unmasking microarray in combination with tissue expression patterns identified novel cancer-specific methylation in each organ site, and we tabulated methylation frequency for each type of cancer. (Results) (1) In esophageal squamous cell carcinoma, we discovered cancer-specific methylation for NEFH (84%), NMDAR2B (78%), DCC (74%), cyclin A1 (60%), CRBP1 (52%), HOPX (50%), trypsinogen-4 (50%), and PGP9.5 (42%). (2) In gastric adenocarcinoma, we validated cancer-specific methylation for HOPX (87%), Reprimo (78%), PGP9.5 (70%), NMDAR2B (70%), and RIZ1 (40%). (3) In colorectal adenocarcinoma, we identified cancer-specific methylation for Beta 4 GalT1 (82%), Oncostatin MR (80%), DFNA5 (65%), LIFR (65%), and HOPX (52%). (4) From our estimates, about 300 genes were frequently methylated specifically in cancer tissues, and among them, and around 70% of these genes were upstream or downstream of the p53 pathway (NMDAR2AB, DCC, cyclin A1, PGP9.5, HOPX, Reprimo, DFNA5). Apoptotic pathways other than those in the p53 pathway, including death receptor signaling was also observed. Another 30% of methylated genes antagonize unique oncogenic pathways in individual cancers. Either NEFH or HOPX was involved in inactivation of pAkt through an unknown mechanism or PTEN induction in ESCC. RIZ1 uniquely inactivated in gastric cancer, is an inhibitor of the IGF receptor pathway. Oncostatin M R or LIFR in CRC are inhibitors of pStat3. All inactivated TSG candidates were demonstrated to be robustly reactivated by de-methylating agents. (Conclusion) In GI cancers, numerous genes involved in p53 activation are commonly suppressed in expression, and epigenetic reversion of p53 activity may be beneficial for killing cancer cells more efficiently. Moreover, unique oncogenic inhibitors will need to be developed for specific targets in similar but related pathways for varied organ sites.
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 963. doi:1538-7445.AM2012-963
Abstract 971: Identification of BCL6 targeted therapies for breast cancer through gene expression networks
Authors: Walker Sarah R. , Cerchietti Leandro C. , Nicolais Maria C. , Yuan Guo-Cheng , Melnick Ari , Frank David A. 
Published: August 2012

Abstract
Breast cancer remains a deadly disease for countless women, thus new treatment strategies must be developed. Since inappropriate activation of transcription factors is a common pathogenic event in breast cancer, targeting these proteins may be a tractable new strategy. In particular, we have found that the BCL6 transcriptional modulator is expressed in 11 out of 12 breast cancer cell lines. In addition, BCL6 has been reported to be expressed in the majority of high-grade ductal carcinomas. Importantly, inhibiting BCL6 expression by RNA interference reduced cell survival. We hypothesized that BCL6 target gene expression profiles could be used to identify compounds with BCL6 inhibitory activity. To generate a breast cancer specific BCL6 gene signature, we employed the combination of gene expression microarrays and BCL6 binding sites identified by ChIP-seq in breast cancer cells. These BCL6 target gene profiles were then used to interrogate the Connectivity Map, a compilation of gene expression signatures reflecting the effects of more than 1300 compounds. This allowed us to identify compounds whose gene expression signature was the inverse of that mediated by BCL6, and might thereby function as BCL6 inhibitors. We screened six of these compounds for BCL6 inhibitory activity using a BCL6-specific reporter which identified disulfiram, celastrol, and harmol as inhibitors of the transcriptional repressor effects of BCL6. Importantly, treating breast cancer cells with these compounds reduced the viability of these cells. Moreover, combining these compounds with cytotoxic agents used in breast cancer therapy enhanced cell killing. In addition, combining these agents with a peptidomimetic of BCL6 also enhanced cell killing. Taken together, these studies show that BCL6 is a key therapeutic target in breast cancer, and that gene signature analysis can be used to identify novel inhibitors of this protein that have activity in breast 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 971. doi:1538-7445.AM2012-971
Abstract 974: New target discovery for oncology utilizing phenotypic selection and primary NSCLC patient tumors
Authors: Holoweckyj Nicholas M. , Sandercock Alan , Guillard Sandrine , Rust Steven , Hay Carl , Brand Erin , Meekin John , Huang Qihui , Sachsenmeier Kris , Hollingsworth Robert E. , Minter Ralph , Bowden Emma 
Published: August 2012

Abstract
Lung cancer is the most common type of cancer, with approximately 222,000 new cases expected each year in the United States. Approximately 72% of the individuals diagnosed with lung cancer will fall victim to the disease. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, but current treatments will not cure the disease for most patients. In an effort to identify novel therapeutics to address this unmet need, a phenotypic screening campaign was initiated. This type of target identification approach allows the discovery of novel drug targets by selection of antibodies based on their ability to elicit a specific desired phenotype. Once antibodies with the desired function are isolated, the targets to which the “hit” antibodies bind can be identified using a variety of approaches including IP-mass spec. Although phenotypic screens have been performed previously, the current effort has important advantages over those described previously. Specifically, this included the use of several unique screening assays run in parallel to allow the evaluation of multiple phenotypes simultaneously. Also unique was the use of primary material from NSCLC patients for both selection and functional screening. Specifically, we demonstrate the use of primary tumor cells in high throughput screening assays. We show the utility of incorporating novel screening assays including anoikis and spheroids with multiple endpoint readouts. Finally we provide data describing a series of “hit” antibodies isolated in the screen which had a variety of activities across the screening assays. These studies show the utility of function-first screening in the identification of unique potential therapeutic targets for oncology.
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 974. doi:1538-7445.AM2012-974
Abstract 983: Wnt pathway activation involves inhibition of β-catenin ubiquitination within the endogenous Axin1 complex
Authors: Li Vivian SW , Ng Ser Sue , Karthaus Wouter R. , Gerlach Jan P. , Mohammed Shabaz , Heck Albert , Maurice Madelon M. , Mahmoudi Tokameh , Clevers Hans 
Published: August 2012

Abstract
Degradation of cytosolic β-catenin by the APC/Axin1 Destruction Complex represents the key regulated step of the Wnt pathway. It is incompletely understood how the Axin1 complex exerts its Wnt-regulated function. We have now examined the compositional change of the endogenous Axin1 complex in HEK293T cells upon Wnt signaling. Our results demonstrate that not only phosphorylation, but also ubiquitination and proteasomal degradation of β-catenin occur within the Axin1 complex. In disagreement with current views, we find neither a disassembly of the complex, nor an inhibition of phosphorylation of Axin1-bound β-catenin upon Wnt signaling. Comparable observations are made in primary intestinal epithelium and in colorectal cancer cell lines carrying activating Wnt pathway mutations. Wnt signaling induces the loss of the dedicated E3 ligase α-TrCP from the complex, leading to complex saturation by accumulated phospho-β-catenin. Subsequently, newly synthesized β-catenin can accumulate in a free cytosolic form, travel to the nucleus and engage the TCF Wnt effector transcription factors. In contrast to current belief, the Axin complex remains compositionally intact in APC-mutant colorectal cancer. Rather, failure of β-catenin ubiquitination is the principle biochemical activating event in these malignant cells. Together we demonstrate a novel mechanism of the destruction complex for Wnt signal activation in both physiological and malignant states.
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 983. doi:1538-7445.AM2012-983