bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drug Efflux by Breast Cancer Resistance Protein Is a Mechanism of Resistance to the Benzimidazole Insulin-Like Growth Factor Receptor/Insulin Receptor Inhibitor, BMS-536924
Authors: Hou Xiaonan , Huang Fei , Carboni Joan M. , Flatten Karen , Asmann Yan W. , Ten Eyck Cynthia , Nakanishi Takeo , Tibodeau Jennifer D. , Ross Douglas D. , Gottardis Marco M. , Erlichman Charles , Kaufmann Scott H. , Haluska Paul 
Published: January 2011

Abstract
Preclinical investigations have identified insulin-like growth factor (IGF) signaling as a key mechanism for cancer growth and resistance to clinically useful therapies in multiple tumor types including breast cancer. Thus, agents targeting and blocking IGF signaling have promise in the treatment of solid tumors. To identify possible mechanisms of resistance to blocking the IGF pathway, we generated a cell line that was resistant to the IGF-1R/InsR benzimidazole inhibitors, BMS-554417 and BMS-536924, and compared expression profiles of the parental and resistant cells lines using Affymetrix GeneChip Human Genome U133 arrays. Compared with MCF-7 cells, breast cancer resistance protein (BCRP) expression was increased 9-fold in MCF-7R4, which was confirmed by immunoblotting and was highly statistically significant (P = 7.13E-09). BCRP was also upregulated in an independently derived resistant cell line, MCF-7 924R. MCF-7R4 cells had significantly lower intracellular accumulation of BMS-536924 compared with MCF-7 cells. Expression of BCRP in MCF-7 cells was sufficient to reduce sensitivity to BMS-536924. Furthermore, knockdown of BCRP in MCF-7R4 cells resensitized cells to BMS-536924. Four cell lines selected for resistance to the pyrrolotriazine IGF-1R/InsR inhibitor, BMS-754807, did not have upregulation of BCRP. These data suggest that benzimidazole IGF-1R/InsR inhibitors may select for upregulation and be effluxed by the ATP-binding cassette transporter, BCRP, contributing to resistance. However, pyrrolotriazine IGF-1R/InsR inhibitors do not appear to be affected by this resistance mechanism. Mol Cancer Ther; 10(1); 117–25. ©2011 AACR.
Lysophosphatidylcholine Pretreatment Reduces VLA-4 and P-Selectin–Mediated B16.F10 Melanoma Cell Adhesion In vitro and Inhibits Metastasis-Like Lung Invasion In vivo
Authors: Jantscheff Peter , Schlesinger Martin , Fritzsche Juliane , Taylor Lenka A. , Graeser Ralph , Kirfel Gregor , Fürst Dieter O. , Massing Ulrich , Bendas Gerd 
Published: January 2011

Abstract
Lysophosphatidylcholine (LysoPC) is an important intermediate in degradation and biosynthesis of phosphatidylcholine (PC). Reduced plasma LysoPC levels observed in patients with advanced cancer indicate a deregulation of LysoPC metabolism in metastasis. Recent data showed strong antimetastatic effects of liposomes consisting of saturated PC in a murine pancreatic metastasis model. LysoPC, generated from saturated PC after accumulation of the liposomes in tumor tissue, might be contributing to these effects. Examining effects of high local concentrations of saturated LysoPC and investigating potential molecular mechanisms, fast removal of saturated LysoPC from medium by murine B16.F10 melanoma cells and radical shifts in tumor cell membrane fatty acid (FA) composition toward saturated FAs were observed in vitro. Scanning electron microscopy revealed remarkable morphologic surface changes of LysoPC-treated tumor cells, probably causing their impaired migratory ability on fibronectin. A LysoPC concentration exceeding a threshold of about 400 μmol/L, slightly above physiologic levels, strongly reduced VLA-4–mediated binding of B16.F10 cells to VCAM-1 as well as P-selectin–dependent interaction with activated platelets, although expression levels were not altered. These findings were reflected in a syngenic intravenous lung invasion model using repeatedly ex vivo LysoPC-treated (450 μmol/L) B16.F10 cells, resulting in significantly reduced lung metastasis-like lesions (−48.3%, P = 0.006). Prior application of 50 IU unfractionated heparin further reduced lung invasion (−81.6%, P = 0.043). Our work shows for the first time that saturated LysoPC in high concentrations reduces melanoma cell adhesion in vitro and hematogeneous dissemination in vivo by direct ex vivo tumor cell targeting. Mol Cancer Ther; 10(1); 186–97. ©2011 AACR.
Prediction of Colorectal Cancer Relapse and Prognosis by Tissue mRNA Levels of NDRG2
Authors: Chu Dake , Zhang Zixi , Li Yunming , Wu Lin , Zhang Jing , Wang Weizhong , Zhang Jian 
Published: January 2011

Abstract
NDRG2 (N-Myc downstream-regulated gene 2) is aberrantly expressed in colorectal cancer (CRC) and related to tumor differentiation status. In the present study, we investigated the association between NDRG2 mRNA levels in primary CRC to determine whether levels of NDRG2 mRNA could predict relapse and survival. A hospital-based study cohort of 226 CRC patients was involved in the study. NDRG2 mRNA levels were determined by real-time PCR. Correlations of NDRG2 mRNA expression with tumor clinicopathologic features, disease-free survival, and overall survival of the patients were studied. Significant decreased expression of NDRG2 mRNA was detected in tumor specimens. NDRG2 mRNA expression significantly correlated with differentiation status (P &lt; 0.001), lymph node metastasis (P &lt; 0.001), and tumor node metastasis stage (P &lt; 0.001). Patients with reduced level of NDRG2 mRNA had a statistically significantly shorter disease-free survival and overall survival duration than patients with preserved expression of NDRG2 mRNA. In multivariate analysis, NDRG2 mRNA level was found to be an independent prognostic factor for both disease-free survival and overall survival of CRC patients. The present research provided the first evidence that decreased NDRG2 mRNA expression in primary human CRC might be a powerful, independent predictor of recurrence and outcome. Mol Cancer Ther; 10(1); 47–56. ©2011 AACR.
MEK/ERK Inhibitor U0126 Increases the Radiosensitivity of Rhabdomyosarcoma Cells In vitro and In vivo by Downregulating Growth and DNA Repair Signals
Authors: Marampon Francesco , Gravina Giovanni Luca , Di Rocco Agnese , Bonfili Pierluigi , Di Staso Mario , Fardella Caterina , Polidoro Lorella , Ciccarelli Carmela , Festuccia Claudio , Popov Vladimir M. , Pestell Richard G. , Tombolini Vincenzo , Zani Bianca Maria 
Published: January 2011

Abstract
Multimodal treatment has improved the outcome of many solid tumors, and in some cases the use of radiosensitizers has significantly contributed to this gain. Activation of the extracellular signaling kinase pathway (MEK/ERK) generally results in stimulation of cell growth and confers a survival advantage playing the major role in human cancer. The potential involvement of this pathway in cellular radiosensitivity remains unclear. We previously reported that the disruption of c-Myc through MEK/ERK inhibition blocks the expression of the transformed phenotype; affects in vitro and in vivo growth and angiogenic signaling; and induces myogenic differentiation in the embryonal rhabdomyosarcoma (ERMS) cell lines (RD). This study was designed to examine whether the ERK pathway affects intrinsic radiosensitivity of rhabdomyosarcoma cancer cells. Exponentially growing human ERMS, RD, xenograft-derived RD-M1, and TE671 cell lines were used. The specific MEK/ERK inhibitor, U0126, reduced the clonogenic potential of the three cell lines, and was affected by radiation. U0126 inhibited phospho-active ERK1/2 and reduced DNA protein kinase catalytic subunit (DNA-PKcs) suggesting that ERKs and DNA-PKcs cooperate in radioprotection of rhabdomyosarcoma cells. The TE671 cell line xenotransplanted in mice showed a reduction in tumor mass and increase in the time of tumor progression with U0126 treatment associated with reduced DNA-PKcs, an effect enhanced by radiotherapy. Thus, our results show that MEK/ERK inhibition enhances radiosensitivity of rhabdomyosarcoma cells suggesting a rational approach in combination with radiotherapy. Mol Cancer Ther; 10(1); 159–68. ©2011 AACR.
Targeting Tyrosine Phosphorylation of PCNA Inhibits Prostate Cancer Growth
Authors: Zhao Huajun , Lo Yuan-Hung , Ma Li , Waltz Susan E. , Gray Jerilyn K. , Hung Mien-Chie , Wang Shao-Chun 
Published: January 2011

Abstract
The proliferation cell nuclear antigen (PCNA) is a critical protein required for DNA replication in proliferating cells including cancer cells. However, direct inhibition of PCNA in cancer cells has been difficult due to the lack of targetable sites. We previously reported that phosphorylation of tyrosine 211 (Y211) on PCNA is important for the proliferative function of PCNA when this protein is associated with the chromatin in cancer cells. Here, we show that the Y211 phosphorylation of PCNA is a frequent event in advanced prostate cancer. To explore the potential of this signaling event in inhibition of cancer cell growth, we used a synthetic peptide, the Y211F peptide, which when present inhibits phosphorylation of Y211 on endogenous PCNA. Treatment with this peptide, but not a scrambled control peptide, resulted in S-phase arrest, inhibition of DNA synthesis, and enhanced cell death in a panel of human prostate cancer cell lines. In addition, treatment with the Y211F peptide led to decreased tumor growth in PC3-derived xenograft tumors in vivo in nude mice. Our study shows for the first time that PCNA phosphorylation at Y211 is a frequent and biologically important signaling event in prostate cancer. This study also shows a proof of concept that Y211 phosphorylation of PCNA may be used as a therapeutic target in prostate cancer cells, including cells of advanced cancers that are refractory to standard hormonal therapies. Mol Cancer Ther; 10(1); 29–36. ©2011 AACR.
Abstract A100: STAT3 as a novel cancer prevention target in colorectal cancer stem cells
Authors: Lin Li , Li Chenglong , Li Pui-Kai , Fuchs James , Lin Jiayuh 
Published: January 2011

Abstract
Constitutive activation of signal transducers and activators of transcription 3 (STAT3) signaling is frequently detected in human cancer including colon cancer, and has emerged as an attractive molecular target for cancer prevention. Recent experimental evidence suggests that the existence of a small population of tumorigenic stem/progenitor cells may be responsible for tumor initiation, chemotherapy and radiation resistance, invasion, recurrence, and metastasis. An increasing body of evidence suggests that the cancer stem cell concept is also relevant to colorectal cancer. To date, however, whether STAT3 is activated in colon cancer stem cells or cancer-initiating cells and what the role of STAT3 signaling may play in these cancer stem cells is still unknown. If STAT3 is activated in colorectal cancer stem cells, inhibiting STAT3 may offer a promising opportunity to target colorectal cancer stem cells and prevent the recurrence of cancer. We utilized the colon cancer stem cells, which are characterized by an aldehyde dehydrogenase (ALDH)-positive (ALDH+) and CD133-positive (CD133+) subpopulation. We demonstrated that ALDH+/CD133+ cells have capacity than ALDH-/CD133- cells to form more tumorspheres and to exhibit more potent tumor-initiating ability in mice. We then examined the STAT3 activation in these colon cancer cells. Interestingly, we observed that the ALDH+/CD133+ subpopulation of colon cancer cells expressed higher levels of phosphorylated STAT3, an active form of STAT3, compared to the ALDH-/CD133- subpopulation and un-separated colon cancer cells, suggesting that STAT3 is activated in colon cancer stem cells. We demonstrated that dietary agent, curcumin and a new curcumin analog, GO-Y030 can inhibit STAT3 phosphorylation, cell viability, and induced apoptosis in colon cancer stem cells. The inhibition of STAT3 was confirmed using a novel STAT3-selecitve curcumin analog, FLLL32, STAT3 ShRNA, as well as STAT3 inhibitors, LLL12 and Stattic. All these STAT3 inhibitors, inhibited STAT3 phosphorylation, cell viability, and tumorsphere growth in colon cancer stem cells. Furthermore, both GO-Y030 and LLL12 inhibited tumor growth of colon cancer stem cells in NOD/SCID mouse model in vivo. In Summary, this is the first report to demonstrate that persistent STAT3 phosphorylation is expressed in colon cancer stem cells. Our study is also the first attempt to target STAT3 in colon cancer stem cells and we demonstrated for the first time that colon cancer stem cells are indeed sensitive to the inhibition by small molecular STAT3 inhibitors, FLLL32, LLL12, Stattic, STAT3 shRNA, and curcumin analog, GO-Y030. Our results suggest that STAT3 is a novel prevention target in colon cancer stem cells and inhibition of activated STAT3 in cancer stem cells may offer an effective preventive approach for colorectal carcinoma.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A100.
Abstract A102: Chemopreventive efficacy and mechanistic studies of Targretin in the B[a]P-induced mouse lung tumor prevention model
Authors: Sharma Sheela , Lee Jin , Zhou Jianliang , Steele Vernon E. 
Published: January 2011

Abstract
Aspiration route has been demonstrated to be as effective as inhalation in administering agents to lung with associated reduction in cost for equipment and chemopreventive agent. The current study evaluated the chemopreventive efficacy and mechanism (s) of Targretin, a novel oral synthetic retinoid that selectively binds and activates retinoid X receptors, via oropharyngeal aspiration against the strain A/J mouse lung adenoma induced by benzo[a]pyrene (B[a]P). Lung adenomas were induced in 8-week old female strain A/J mice by three oral gavages of B[a]P (2 mg /0.2 ml cotton seed oil). The mice were allowed 4 weeks to develop dysplasia, then given one of three doses of Targretin (0.1, 0.3 and 1 mg/kg) for 16 weeks. At different time points, the expression of a series of biomarkers (e.g., Cox-2 and 5-Lox at 2 and 16 weeks, survivin, PCNA and apoptosis at 16 weeks) in lung was evaluated by Western Blot and immunohistochemistry. Tumor incidence and multiplicity in the lung were measured following 16-week aspiration of Targretin and compared with B[a] P only group. Targretin showed dose-related inhibition of B[a]P-induced tumor incidence (p&lt;0.05) at 0.1 and 0.3 mg/kg following 16-week treatment with no effect on tumor multiplicity. Targretin also showed dose-dependent inhibition of 5-Lox (25-47%) at 2 and 16 weeks, and Cox-2 (27-38%) and survivin (39-48%) at 16 weeks. A dose-dependent induction of apoptosis (2.2-3.0-fold) and a marginal but dose-dependent inhibition of PCNA were also observed at 16 weeks. In conclusion, this study demonstrated that Targretin via aspiration showed chemopreventive efficacy against mouse lung adenoma with good correlation to early and late biomarkers of lung cancer progression. Also, it indicated that the aspiration route can be an excellent inexpensive alternative to inhalation for direct drug delivery to the rodent lung for efficacy testing of potential chemopreventive agents (Supported by NCI #N01-CN-53301).
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A102.
Abstract A107: Epigenetic markers for tissue-based breast cancer risk stratification
Authors: Euhus David M. , Bu Dawei , Rao Roshni , Leitch Marilyn , Lewis Cheryl 
Published: January 2011

Abstract
Effective breast cancer risk management requires accurate breast cancer risk stratification. The Gail model is the most widely used and best validated epidemiological risk assessment model. Though well calibrated, this model is not ideal for individualized risk counseling as it is only 8% better than chance for discriminating between women with breast cancer and unaffected women. Biologically based approaches, such as cytological assessment of nipple aspirate fluid or assessment of mammographic density, only marginally improve the discrimination of the Gail model. Promoter region methylation is one of the earliest identifiable molecular changes during breast carcinogenesis. We have previously shown that RASSF1A methylation, detected in benign breast epithelium obtained by random periareolar fine needle aspiration biopsy (RP-FNA), is associated with increased breast cancer risk, but this was based primarily on correlation with Gail risk and not cancer case prediction. A clinically useful epigenetic risk stratification panel would be ideally suited to benign RP-FNA samples and would provide a high degree of discrimination between benign samples from women with cancer and unaffected women. We performed a genome-wide 5-aza-2’-deoxycytidine (5-aza) induced gene re-expression screen in 6 breast cancer cell lines and 6 early passage primary benign breast epithelial cell cultures to identify potential epigenetic markers of breast cancer risk. MSP assays were designed for the 286 genes that were 1) expressed in benign breast epithelium, 2) not expressed in cancer, and 3) induced by 5-aza in cancer, or 4) had previously shown some potential for breast cancer risk stratification. 20 genes were identified that were frequently methylated in primary breast cancer, rarely methylated in benign RP-FNA samples and never methylated in lymphocytes. Quantitative multiplex methylation-specific PCR assays were designed and optimized for the 17 best genes and then assessed in an archival RP-FNA sample set that included 146 samples from unaffected women, 59 benign samples from breast cancer patients, and 52 primary breast cancers. A three marker panel including PSAT1, HS3ST2, and GNE provided the best discrimination between benign samples from cancer patients and unaffected women. One or more of these markers was scored as positive in 46% of benign samples from cancer patients, 8% of samples from unaffected patients, and 72% of primary cancers. The odds ratio for cancer case prediction based on assessment of benign RP-FNA samples was 9.42 (95% CI 4.31 — 20.59, p &lt; 0.0001). These observations will be validated in an independent set of 160 sample prospectively acquired for this purpose. These data suggest that a limited epigenetic marker panel can detect a small population of breast cells accessible by RP-FNA whose presence is associated with significantly increased breast cancer risk.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A107.
Abstract A108: Phosphoprotein network activation during breast cancer initiation
Authors: Seewaldt Victoria L. , Ibarra-Drendall Catherine , Pilie Patrick , Barry William , Broadwater Gloria , Petricoin Emanuel 
Published: January 2011

Abstract
Background: Currently we lack the ability to rapidly test new agents to prevent breast cancer. Targeted agents are in clinical testing for treatment of breast cancer but are not being adequately explored for prevention. This is because, without biomarkers to select women that are most likely to respond and rapidly evaluate response, Phase I/II testing of targeted agents for prevention will be too risky and expensive. Single biomarkers have been traditionally used to evaluate response to chemotherapeutic agents. However, single biomarkers may not be adequate to evaluate the complex phosphorylation network signaling events that occur during breast cancer initiation. Furthermore, emerging evidence suggests that resistance to targeted agents may occur through paradoxical activation of quiescent signaling pathway. As a result, it has become increasingly important to monitoring network signaling in women receiving targeted agents.
Targeted agents that have low-toxicity profiles and have inhibitory activity against breast cancer cell proliferation and/or invasion may show promise as a prevention agent. However, before any given targeted agent could be tested for pilot prevention trials, we first need to identify 1) signaling pathway(s) that are affected by the drug in preclinical models of breast cancer, 2) short-term and long-term consequences of treatment, 3) potential biomarker(s) to closely track response.
Methods and Results: We tested for protein network signaling in cytological specimens in women at high-risk for breast cancer. Our group used reverse-phase protein microarray (RPPM) platform to test for proteomic signatures of short-term risk to breast cancer. RPPM was developed to provide reproducible assessment of 50 phospho-proteins in 5,000 epithelial cells. Initial signature testing was performed in mammary cytology obtained from two groups of 50 high-risk women undergoing Random Periareolar Fine Needle Aspiration (RPFNA). Unsupervised heirachal clustering of RPPM proteomic analysis RPFNA aspirates from high-risk women identified three activated signaling pathways 1) Akt/mTOR/PI3K/cSrc, 2) EGRF/MEK/ERK, and 3) HER2/bcl-2.
Conclusion: Here we demonstrate our ability to identify activated phospho-protein signaling pathways in limited RPFNA cytology. The power of this approach is that we can use a combination of RPPM and RPFNA to track response to any new targeted prevention agents. Importantly, we are able to validate our proteomic signatures in parallel nanobiosensor testing of live atypical RPFNA cytology from women in our high-risk cohort.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A108.
Abstract A13: Short-chain fatty acids (SCFA) induced autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death
Authors: Tang Yong , Chen Yakun , Jiang Hongmei , Nie Daotai 
Published: January 2011

Abstract
Short-chain fatty acids (SCFAs) are the major by-products of bacterial fermentation of undigested dietary fibers in the large intestine. SCFAs, mostly propionate and butyrate, inhibit proliferation and induce apoptosis in colon cancer cells, but clinical trials had mixed results regarding the anti-tumor activities of SCFAs. Herein, we demonstrate that propionate and butyrate induced autophagy in human colon cancer cells to dampen apoptosis whereas inhibition of autophagy potentiated SCFA-induced apoptosis. Colon cancer cells, after propionate treatment, exhibited extensive characteristics of autophagic proteolysis: increased LC3-I to LC3-II conversion, acidic vesicular organelle development, and reduced p62/SQSTM1 expression. Propionate-induced autophagy was associated with decreased mTOR activity and enhanced AMP kinase activity. The elevated AMPKalpha phosphorylation was associated with cellular ATP depletion and overproduction of reactive oxygen species due to mitochondrial dysfunction involving the induction of MPT and loss of membrane potentials. In this context, mitochondria biogenesis was initiated to recover cellular energy homeostasis. Importantly, when autophagy was prevented either pharmacologically (3-MA or chloroquine) or genetically (knockdown of ATG5 or ATG7), the colon cancer cells became sensitized toward propionate induced apoptosis through activation of caspase-7 and caspase-3. The observations indicate that propionate-triggered autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death, whereas application of an autophagy inhibitor (Chloroquine) is expected to enhance the therapeutic efficacy of SCFAs in inducing colon tumor cell apoptosis.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A13.