bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1213: Neuropeptide Y, adipose tissue and breast cancer
Authors: Ngan Emily , Labus Andrea , Cowen Sarah , Vona-Davis Linda 
Published: June 2012

Abstract
Adipose tissue contributes to obesity-associated risk in breast cancer progression. Recent work has demonstrated the involvement of preadipocytes in promoting the induction of breast tumor cell migration and invasion. Neuropeptide Y (NPY) stimulates proliferation of preadipocytes in vitro by the Y1 receptor. NPY receptors are present in almost all primary breast cancers and in lymph node metastases from ER-positive primary cancers. By contrast, the peptide has been shown to inhibit the invasion of certain tumor cells. However, the relative contribution of adipose and NPY to breast tumor survival remains to be determined. Using the highly metastatic ER-negative human breast cancer cell line MDA-MB-231, we found that NPY significantly inhibited cell proliferation, an effect that was reversed by treatment with the Y1-receptor antagonist BIBP-3226 (P&lt;0.05). Breast tumor cells treated with NPY exhibited changes in cell morphology and demonstrated a two-fold increase in early apoptosis. When breast tumor cells were incubated in the presence of conditioned media harvested from 3T3-L1 preadipocytes, NPY enhanced apoptosis. Significantly more breast tumor cells migrated toward the preadipocytes compared to conditioned media alone (P&lt;0.0001), but less in the presence of NPY. In conclusion, it appears that adipose tissue promotes breast tumor survival and migration, while NPY limits its. It will be of interest to determine whether the tumor migration-promoting activity of preadipocytes varies among breast cancer subtypes, and if so, whether it serves as a predisposing factor for breast cancer progression. In addition, the targeting of NPY-Y1 receptors in breast tumors may have a diagnostic and possibly therapeutic value.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1213. doi:10.1158/1538-7445.AM2011-1213
Abstract 1240: Characterization of Notch3 in senescence regulation and tumor suppression
Authors: Cui Hang , Zhang Hong 
Published: June 2012

Abstract
Notch signaling has been shown to regulate a broad spectrum of cell fate decisions and differentiation. However, very little is known about the role of Notch signaling in cellular senescence. Here we report that the level of Notch3, a member of Notch transmembrane receptors, is specifically elevated in human fibroblasts during senescence induced by different senescence stimuli. This up-regulation of Notch3 is required for the induction of p21 in senescent cells, whereas adventitious expression of Notch3 in early passage fibroblasts induces senescence accompanied by p21 elevation. Furthermore, we find that Notch3-mediated senescence requires a canonic Notch singling, and deletion of p21 can partially abolish Notch3-induced senescence. The expression of Notch3 is undetectable in a number of human cancer cell lines, and restored expression of Notch3 in these cancer cell lines with undetectable level of Notch3 leads to proliferative arrest. Interestingly, the expression of Notch3 in the luminal subtype of human breast cancer is significantly decreased as compared to other subtypes of breast cancer. More importantly, low level of Notch3 expression in patients with luminal type of breast cancer correlates significantly with poor clinical prognosis. Our results reveal a novel function of Notch3 in senescence regulation and tumor suppression, suggesting that modulation of Notch3 provides a potential therapeutic approach for luminal subtype of breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1240. doi:10.1158/1538-7445.AM2011-1240
Abstract 1246: Role of PKCα and G3BP in stress granule formation
Authors: Winslow Sofia , Kobayashi Tamae , Sunesson Lovisa , Larsson Christer 
Published: June 2012

Abstract
Cells exposed to environmental stress protect themselves from damage by regulation of protein synthesis. Translation of certain proteins is being inhibited at mRNA level in order to influence repair mechanisms. The untranslated mRNAs are assembled into cytoplasmic complexes known as stress granules and will be stalled in this formation until translation is resumed or mRNA is degraded. Apart from mRNA, stress granules contain several proteins with more or less known function for this response. Proteins involved in mRNA stability, e.g. HuR (Hu Protein R), and other RNA-binding proteins are established members in stress granules, whereas heat shock proteins are excluded. Even though many of the constituents of the stress granules are know, the mechanisms behind the formation of stress granules and what role certain proteins have in these complexes are still not fully known.
Ras-GAP binding protein (G3BP) is an mRNA-binding protein that relocates into stress granules upon heat shock and we have data showing that the serine/threonine kinase Protein kinase Cα (PKCα) is recruited to the same complex. We aimed to investigate the role of G3BP and PKCα in stress granule formation and study the interaction between G3BP and PKCα.
Protein interactions between the stress granule proteins PKCα and G3BP, mediated by the C1a-domain of PKCα and the RRM domain of G3BP, were studied in vivo with immunoprecipitation of exogenous constructs as well as in vitro with pull down of pure protein constructs. We further investigated the necessity of PKCα and G3BP in stress granule formation by knocking down the proteins with siRNA. Our data indicate that both proteins are of importance for optimal stress granule formation, but depending on the type of stress, the proteins seem to be of different importance.
Taken together, our results indicate that PKCα have a role in stress granule formation via the RNA-binding protein G3BP.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1246. doi:10.1158/1538-7445.AM2011-1246
Abstract 1248: Enhanced glutamine metabolism contributes to docetaxel resistance in DU145 prostate cancer cells
Authors: Rajagopalan Kartik N. , Marian Calin O. , Shay Jerry W. , DeBerardinis Ralph J. 
Published: June 2012

Abstract
Chemotherapeutic resistance is one of the major factors contributing to cancer mortality. Although evidence supports a mechanistic link between metabolic enzyme polymorphisms and drug sensitivity, little is known about the metabolic changes tumor cells undergo when treated with a chemotherapeutic agent. Moreover, the metabolic consequences of exposure to these agents may provide essential adaptive functions contributing to chemotherapeutic resistance. Here we used metabolic flux analysis to identify metabolic changes accompanying and potentially accounting for docetaxel resistance in DU145 prostate cancer cells. We focused on the utilization of glucose and glutamine, the two most abundant extracellular nutrients, which together account for the bulk of carbon and nitrogen metabolism in tumor cells. Docetaxel resistant (DOCETR) cells consumed glutamine more avidly and secreted glutamate and ammonia at a greater rate than sensitive parental cells. Surprisingly, contribution of glutamine carbon into the TCA cycle was unchanged in DOCETR cells despite the higher glutamine utilization. Transfer of glutamine carbon into both the intracellular and extracellular glutamate pools, on the other hand, was higher in DOCETR cells, indicating that the DOCETR cells had an increased ability to convert glutamine to glutamate and then to secrete the glutamate. Accordingly, these cells also had increased expression and activity of glutaminase, the major enzyme responsible for glutamine deamidation. Because glutaminase activity does not yield energy unless the resulting glutamate is further oxidized, we hypothesized that this metabolic transition served a non-bioenergetic role, possibly supporting enhanced rates of glutathione synthesis for modification and secretion of docetaxel. Consistent with this idea, DOCETR cells displayed an increase in de novo synthesis of glycine, which is required for the production of glutathione. Importantly, a glutaminase inhibitor re-sensitized DOCETR cells to docetaxel, strongly suggesting that their enhanced glutamine metabolism was involved in resistance to the drug. We speculate that alterations in glutamine metabolism provide a general and targetable mechanism for xenobiotic resistance in cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1248. doi:10.1158/1538-7445.AM2011-1248
Abstract 1270: Metabolic alterations impair breast cancer cell viability following detachment from the extracellular matrix
Authors: Schafer Zachary T. 
Published: June 2012

Abstract
The ability of cancer cells to survive in the absence of normal matrix is critical for tumor progression and metastasis. Normal (non-tumorigenic) cells that lose attachment to extracellular matrix (ECM) undergo caspase-dependent death (known as anoikis), a phenomenon that is frequently defective in cancer cells. However, recent findings reveal that inhibition of anoikis is not sufficient to allow for cell survival in abnormal matrix environments. We have recently discovered that breast cancer cells must rectify detachment-induced metabolic alterations in order to survive in the absence of ECM attachment.
Using MCF-10A cells, we have discovered that cells that are detached from the ECM exhibit a decrease in ATP levels and glucose uptake that is independent of the anoikis program. Interestingly, the treatment of detached cells with antioxidants is sufficient to elevate ATP levels without affecting glucose uptake, suggesting that ROS contribute to the reduction of ATP levels in detached cells. In addition, overexpression of ErbB2 induces a striking rescue of detachment-induced ATP/glucose uptake deficiencies while lowering cellular ROS levels. We found that pentose phosphate pathway (PPP) generated NADPH is essential for ErbB2 to elevate ATP levels and reduce cellular ROS in detached cells. Furthermore, we have discovered that eliminating cellular ROS on its own is sufficient to enhance the viability of matrix-deprived cells. Using a 3-dimensional cell culture system (in which luminal cells lack ECM contact), we have found that antioxidant treatment promotes the filling of the luminal space.
We have now expanded on these studies and found a role for these detachment-induced metabolic alterations in inflammatory breast cancer cells and have discovered an Akt-independent signaling pathway downstream of oncogenic Ras that also promotes detachment-induced viability. Our current studies are also focused on understanding the role of ROS in regulating ATP generation by fatty acid oxidation. Furthermore, we are examining the role of the tumor microenvironment in the regulation of caspase activation and metabolism in detached epithelial cells. These studies could lead to the identification of novel molecular mechanisms that could be targeted for the selective elimination of ECM-detached cancerous cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1270. doi:10.1158/1538-7445.AM2011-1270
Abstract 1271: Human non small cell lung cancer tissue has enhanced expression of pyruvate carboxylase, but not glutaminase
Authors: Fox Matthew P. , Bousamra Michael , Slone Stephen P. , Lane Andrew N. , Fan Teresa W-M 
Published: June 2012

Abstract
Altered cellular metabolism in tumors is well established, particularly an increased rate of aerobic glycolysis [1]. However, increased glycolysis alone is insufficient to sustain the enhanced cell growth and anabolic metabolism characteristic of cancer. Another key source of these precursors is the citric acid cycle (CAC). Removal of CAC intermediates for anabolism requires replenishment by other sources; these anaplerotic reactions are vital to cancer development. The two major pathways of anaplerosis are glutaminolyis (deamidation and transamination of glutamine to 2-oxoglutarate) [2] and carboxylation of pyruvate to oxaloacetate (OAA), catalyzed by pyruvate carboxylase (PCB) [2].
We have coupled 13C-labeled glucose tracer with stable isotope resolved metabolomics (SIRM), gene microarray, and western blotting to track the anaplerotic PCB pathway in human lung cancer patients. The resected cancer tissue showed increased flux through the PCB pathway, along with increased transcription of the PCB gene and PCB protein expression compared with the adjacent benign lung tissue [3]. We have extended these findings to 50 paired tissue samples, and have correlated them with histological and clinical data. The protein expression of PCB was on average ten-fold higher in the tumor than in the benign lung tissue (p=0.00001, paired t-test). The normalized protein expression correlated with the fraction of the tumor that was identified as cancer cells, indicating that the increased expression was from the cancer cells rather than other lung cell types. Glutaminase was active in the lung tissue, but its expression was not different from, or lower in the tumors than in the benign lung tissue.
These data indicate that in NSCLC, PCB is important in anaplerosis and tumor metabolism. The balance between glycolysis and the choice of different anaplerotic pathways may depend on the tissue types.
References
1. Gillies, R.J. and R.A. Gatenby, Adaptive landscapes and emergent phenotypes: why do cancers have high glycolysis? Journal of Bioenergetics and Biomembranes, 2007. 39(3): p. 251-257.
2. Portais, J.C., P. Voisin, M. Merle, and P. Canioni, Glucose and glutamine metabolism in C6 glioma cells studied by carbon 13 NMR. Biochimie, 1996. 78(3): p. 155-164.
3. Fan, T.W., A.N. Lane, R.M. Higashi, M.A. Farag, H. Gao, M. Bousamra, and D.M. Miller, Altered Regulation of Metabolic Pathways in Human Lung Cancer Discerned by 13C Stable Isotope-Resolved Metabolomics (SIRM)) Molecular Cancer 2009. 8 p. 41.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1271. doi:10.1158/1538-7445.AM2011-1271
Abstract 1273: Metabolic networks and the role of LDHB in breast cancer
Authors: Dennison Jennifer B. , Molina Jennifer R. , Guo Huifang , Mills Gordon B. 
Published: June 2012

Abstract
Gene expression data of breast cancer cell lines and patient tumors reveal several distinct subtypes that demonstrate different metabolic phenotypes. Our goal was to determine what metabolism genes contribute to the metabolic phenotypes. We hypothesized that dichotomous expression of metabolism genes would identify key drivers of cell metabolism. To select candidate genes, we completed a bimodal analysis using microarray data from 59 breast cancer cell lines. To generate a metabolic network, dichotomous genes were selected from known or probable metabolic networks including electron transport, TCA cycle, nutrient transport, pentose phosphate shunt, energy requiring pathways, and glycolysis. Two groups of dichotomously expressed genes emerged from this analysis: TCA cycle anaplerotic genes (including PFKP, GLS) and cataplerotic/biosynthetic genes (including FASN, GLUL, and FBP1). The gene with the highest bimodal index was LDHB that encodes lactate dehydrogenase B. For breast cancer cell lines, LDHB mRNA and protein were most highly expressed in ER-, glycolytic cell lines. LDHB is reported by others to be part of a “MYC signature,” and consistent with this hypothesis, for ER- cell lines, LDHB mRNA levels were highly associated with MYC and glutaminase, a metabolic down-stream target of MYC. For patient tumors, LDHB mRNA expression was also bimodal with the highest expression in basal-like cancers. Elevated expression of LDHB mRNA predicted worse clinical outcomes for patients with Her2 positive and triple negative tumors. Compared to normal-like breast tissue from patients, LDHB mRNA expression was elevated in triple negative tumors. We conclude that LDHB may be a target of MYC and contribute to the glycolytic phenotype of triple-negative tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1273. doi:10.1158/1538-7445.AM2011-1273
Abstract 1279: Loss of PTEN expression in patients treated with PI3K/AKT/mTOR signaling pathway inhibitors
Authors: Janku Filip , Garrido-Laguna Ignacio , Tsimberidou Apostolia M. , Naing Aung , Fu Siqing , Falchook Gerald S. , Abraham Susan C. , Hong David S. , Kurzrock Razelle 
Published: June 2012

Abstract
Background: Loss of PTEN function results in increased PI3K/AKT/mTOR signaling and may predict sensitivity to drugs targeting the PI3K/AKT/mTOR pathway.
Methods: Archival tumor samples from patients (N = 202) with diverse cancers referred to the Clinical Center for Targeted Therapy from October 2009 were tested for cytoplasmatic expression of PTEN on immunohistochemistry. Whenever possible, tumor tissue was also analyzed for PIK3CA, RAS (K-, N-), and BRAF mutations using PCR-based DNA sequencing. Consecutive patients with loss of PTEN expression and any tumor type were treated whenever possible with agents targeting the PI3K/AKT/mTOR signaling pathway.
Results: Overall, 49 (24%) of 202 patients had loss of PTEN expression. In specific tumor types with a minimum of five patients tested, the loss of PTEN expression was most frequent in squamous cell cervical (60%, 3/5 patients), non-small-cell lung (50%, 4/8), renal (50%, 3/6), uterine (41%, 7/17), gastroesophageal junction/gastric (38%, 3/8), breast cancers (25%, 2/8), melanomas (22%, 6/27), and colorectal cancers (20%, 6/30). Tumors with PTEN loss had frequencies of simultaneous mutations in PIK3CA, RAS (K-, N-), BRAF that were similar to patients with PTEN expression. Of the 49 patients with PTEN loss, 29 (median number of prior therapies, 3) were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor. Six of these 29 patients (20.5%) achieved a partial response (PR) (2 uterine cancers, 1 squamous cell cervical cancer; 1 squamous cell head and neck cancer; 1 melanoma; 1 renal cancer) and 8 (27.5%) had stable disease (SD) for &gt;/ = 4 months (total SD&gt;/ = 4 months + PR = 48%). These 29 treated patients had a median progression-free survival of 4.3 months (95% CI, 3.4-5.2).
Conclusion: Loss of PTEN expression was found in 24% of patients with various solid tumors. Fourteen of 29 heavily-pretreated patients (48%) had a PR or SD &gt;/ = 4 months, when treated with a PI3K/AKT/mTOR axis inhibitor, suggesting that matching patients with these inhibitors based on PTEN loss merits further exploration.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1279. doi:10.1158/1538-7445.AM2011-1279
Abstract 1282: Phase I evaluation of STA-1474, a pro-drug of the novel HSP90 inhibitor STA-9090, in dogs with spontaneous cancer
Authors: London Cheryl A. , Bear Misty D. , McCleese Jennifer , Foley Kevin P. , Paalangara Reji , Inoue Takayo , Ying Weiwen , Barsoum James 
Published: June 2012

Abstract
The novel water soluble compound STA-1474 is metabolized to STA-9090, a potent HSP90 inhibitor previously shown to kill canine tumor cell lines in vitro and inhibit tumor growth in the setting of murine xenografts. The purpose of the following study was to extend these observations and investigate the safety and efficacy of STA-1474 in dogs with spontaneous tumors. This was a Phase 1 trial in which dogs with spontaneous tumors received STA-1474 under one of three different dosing schemes. Pharmacokinetics, toxicities, biomarker changes, and tumor responses were assessed. Twenty-five dogs with a variety of cancers were enrolled. Toxicities were primarily gastrointestinal in nature consisting of diarrhea, vomiting, inappetence and lethargy. Upregulation of HSP70 protein expression was noted in both tumor specimens and PBMCs within 7 hours following drug administration. Measurable objective responses were observed in dogs with malignant mast cell disease (n=3), osteosarcoma (n=1), melanoma (n=1) and thyroid carcinoma (n=1), for a response rate of 24% (6/25). Stable disease (&gt;10 weeks) was seen in 3 dogs, for a resultant overall biological activity of 36% (9/25). This study provides evidence that STA-1474 exhibits biologic activity in a relevant large animal model of cancer. Given the similarities of canine and human cancers with respect to tumor biology and HSP90 activation, it is likely that STA-1474 and STA-9090 will demonstrate comparable anti-cancer activity in human patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1282. doi:10.1158/1538-7445.AM2011-1282
Abstract 1286: Pharmacodynamics of oral curcumin in plasma and rectal mucosa in a Phase IIa trial
Authors: Kakarala Madhuri , Carroll Robert E. , Turgeon Kim , Tuck Melissa , Benya Richard V. , Meyskens Frank , Brenner Dean 
Published: June 2012

Abstract
Background: Curcumin, a dietary polyphenol derivative of turmeric, has potent cancer reductive activity in in vivo colon carcinogenesis models. We administered curcumin at doses of 2 g or 4 g to separate groups of 20 healthy human smokers with &gt; 8 aberrant crypt foci (ACF). The 2 g dose showed no ACF reduction while the 4 g dose showed a 46% reduction (p&lt;0.005) We analyzed native curcumin and its conjutes in matched plasma and rectal mucosa biopsy sample from 21 participants at 2g and 18 participants at 4g.
Methods: Curcuminoid products were extracted from homogenized biopsy tissue and ultacentrifuged plasma and evaporated under argon. The separation was performed on a Symmetry® C18 column. The mobile phase used under gradient conditions was 25% acetonitrile with 74.9% containing 0.1% acetic acid (25:74.9:0.1; v/v/v; A) and 100% acetonitrile containing 0.1% acetic acid (99.9:0.1; v/v; B) The flow rate was 0.3 mL/min and injection volume for all samples was 10 µL. The lower limit of detection for curcumin from human plasma was 5 ng/mL and from human colonic mucosa was 50 ng/5mg tissue.
Results: See Table below (summarized by pre and post treatment dose for plasma and mucosal concentrations)
Conclusions: Native curcumin is not detectable in the majority of biopsy and plasma samples. Conjugated curcumin is detectable in all plasma samples and the majority of mucosal biopsies with a significant increase in plasma concentrations at 4g. We postulate the conjugates detected in the rectal mucosa are delivered systemically from absorption and conjugation higher in the gastrointestinal tract and may have biologic activity.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1286. doi:10.1158/1538-7445.AM2011-1286