bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 941: Suppression of the androgen receptor function by c-Jun in prostate cancer via a dual mechanism
Authors: Hsu Chih-Chao , Hu Chang-Deng 
Published: August 2012

Abstract
Androgen receptor (AR) signaling plays a pivotal role in growth and survival of prostate cancer cells. Upon ligand binding, AR translocates into the nucleus and regulates expression of multiple genes through binding their promoter regions. Thus, altered expression and activity of AR contribute to disease progression. Consequently, significant effort has been undertaken to identify and characterize numerous coactivators and corepressors of AR. Here we report that the transcription factor c-Jun, a basic region leucine zipper (bZIP) transcription factor and is an important member of the AP-1 family, acts as a transcriptional repressor to inhibit the AR transcriptional activity. Furthermore, we have found that c-Jun also represses the transcription of AR. Overexpression of c-Jun in LNCaP prostate cancer cells inhibited luciferase reporters driven by the androgen-induced prostate-specific antigen (PSA) promoter, probasin promoter, mouse mammary tumor virus (MMTV) promoter and tandem repeats of androgen response elements in a dose-dependent manner. Conversely, knockdown of c-Jun enhanced androgen-stimulated AR activity in LNCaP cells. To further confirm the results, we generated a doxycycline-inducible c-Jun overexpression LNCaP stable cell line using lentivrial system. Consistent with the results of promoter activity assay, induction of c-Jun by doxycycline inhibited both steady state and androgen-induced PSA mRNA and protein levels. Interestingly, the protein and mRNA of AR were also downregulated when c-Jun was induced, suggesting that c-Jun suppresses AR expression at the transcriptional level. Moreover, c-Jun induction resulted in a significant reduction in cell number, suggesting that c-Jun suppresses LNCaP cell proliferation by antagonizing AR signaling. In summary, our results suggest that c-Jun negatively regulates the AR signaling by a dual mechanism. Future identification of negative regulators of c-Jun expression will provide a new opportunity to develop novel therapeutics.
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 941. doi:1538-7445.AM2012-941
Abstract 943: Characterization of RET and integrin signaling in thyroid tumors
Authors: Lian Eric , Cockburn Jessica , Varma Sonal , Kasaian Katayoon , Jones Steven J.M. , Tron Victor , Wiseman Sam , Mulligan Lois 
Published: August 2012

Abstract
The REarranged in Transfection (RET) tyrosine kinase is important during development of neural crest derived tissues such as the enteric and sympathetic nervous systems, but is also activated in multiple human tumour types. Activating mutations of RET play an important role in thyroid cancers including both papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC). More broadly, recent studies have also shown that RET may be active in other tumour types such as pancreatic and breast cancers, and that the overexpression and activation of RET may be linked to more aggressive disease. In order to explore this link, we have investigated the expression of RET in a large cohort of over 400 thyroid tumour samples of multiple histologies, ranging from benign lesions through to aggressive, metastatic disease by immunhistochemistry using a thyroid tissue microarray. Our data suggest that RET expression may correlate with more aggressive phenotype across a broader spectrum of tumours than previously predicted. We are currently investigating this association further; first by examining the expression of two major RET protein isoforms, RET9 and RET51, in this panel of tumours, and second, by investigating the coexpression of RET with another group of proteins associated with tumour progression, the integrin family. In preliminary studies, we have evaluated RET coexpression with two integrin subunits, ITGB1 and ITGB3. Our data suggest correlation between tumour aggressiveness and coexpression of RET with these integrin subunits. Together, our data provides insight on the role of RET in increasing aggressiveness over a range of tumours.
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 943. doi:1538-7445.AM2012-943
Abstract 949: Disruption of growth hormone signaling improves the efficacy of conventional chemotherapy in a rat model of mammary cancer
Authors: Lantvit Daniel D. , Shen Qi , Yang Jilai , Unterman Terry G. , Swanson Steven M. 
Published: August 2012

Abstract
Epidemiological and laboratory based studies suggest that the growth hormone/insulin-like growth factor I (GH/IGF-I) axis is positively correlated with a variety of different cancer types. In recent years, our research team has developed animal models to explore the role of GH signaling in carcinogenesis. These include rat and mouse models of mammary, prostate and colon cancer in which the GH receptor is knocked out, antagonized or GH itself is knocked out. In all of these models, we observed a significant (50% or more) disruption in carcinogenesis when GH signaling is impaired compared to normal controls. Our initial studies demonstrated that carcinogenesis can be effectively inhibited by the disruption of GH signaling in animals lacking genes for wild-type GH or the GH receptor. These findings are consistent with a recent report by Guevara-Aguirre and colleagues (Sci Transl Med 3: 70ra13, 2011) who found that a population lacking a functional GH receptor (Laron syndrome) were cancer free except for one patient whose ovarian cancer did not recur after chemotherapy. A control cohort of relatives suffered a 20% mortality rate from cancer. The response of the Laron patient's tumor to chemotherapy inspired us to hypothesize that the lack of GH signaling may render a tumor more vulnerable to conventional chemotherapy. To test this hypothesis, we treated 6 Spontaneous Dwarf rats (SDR) with GH (150 μg/kg twice daily) beginning at 3 weeks of age; 6 control rats received vehicle injections. At 4 weeks of age, all rats were exposed to a single injection of the mammary carcinogen N-methyl-N-nitrosourea (50 mg/kg). Once a rat developed a mammary tumor of 1cm in diameter, GH or vehicle injections were halted and doxorubicin (1.25 mg/kg; 6 injections over 2 weeks) treatments began. The dose of doxorubicin that was chosen was lower than that normally used to induce regression in this model. We observed that tumor growth in wild-type rats was stopped and remained static during treatment with doxorubicin. In contrast, the tumors of SDR rats, lacking GH, all regressed in response to doxorubicin treatment (p &lt; 0.005). These data suggest that disrupting GH signaling may enhance the efficacy of conventional anticancer chemotherapy. Pegvisomant, a GH antagonist approved by the FDA for the treatment of acromegaly, or one of several investigational drugs currently under study for the disruption of IGF-I signaling, may serve to translate the findings presented here to the clinic to improve current cancer therapy regimens. This work was supported by NIH grant R01-CA099904.
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 949. doi:1538-7445.AM2012-949
Abstract 951: Preclinical evaluation of Xanthohumol in carcinoid cancer growth in vitro and in vivo
Authors: Kunnimalaiyaan Muthusamy , Ndiaye Mary , McManus Catherine M. , Seiler Nicole L. , Harrison April , Chen Herbert 
Published: August 2012

Abstract
Background: Besides surgery, there is no potential curative treatment for carcinoid tumors. Because these cancers are metastatic in nature and produce excessive amounts of various bioactive hormones, patients diagnosed with this malignancy will have poor quality of life due to carcinoid syndrome. Therefore, new anticarcinogenic agents are required to improve the effectiveness of treatment. Xanthohumol (XN) (Tetrahydroxy-3′-prenylchalcone) is a prenylated chalconoid found in hops and beer that has been found to have potential anticancer and bioactive properties. Therefore, the purpose of this study was to evaluate the effectiveness of xanthohumol (XN) on carcinoid cancer growth in vitro and in vivo. Methods: To examine the anticancer activity of XN, we treated human gastrointestinal carcinoid BON and bronchopulmonary carcinoid H727 cells with up to 15 μmol/L of XN or carrier (DMSO), and analyzed the effect on cell growth by colony formation assay. The mechanism of growth inhibition was examined by flow cytometry and western analysis for the levels of pro-apoptotic and cell cycle regulatory proteins. To examine the anticancer activity of XN in vivo, subcutaneous BON carcinoid tumors developed in murine xenografts were subjected to intraperitoneal injections of XN (3 mg/kg bwt) or an appropriate volume of DMSO carrier every other day. Results: Treatment with xanthohumol significantly reduced the ability of carcinoid cells to form colonies in a dose-dependent manner. Flow cytometry and western analysis confirmed the observed decrease in cell viability, and showed the decrease was mediated through apoptosis. The carcinoid tumors in the mouse xenograft experiment showed a significant reduction in growth. Conclusions: XN treatment reduced cell viability, colony forming ability and increased cell death through apoptosis. In addition, administration of XN suppressed cancer cell growth in an in vivo xenograft mouse model. Our findings demonstrate for the first time the anti-proliferative effects of xanthohumol in carcinoid cell lines in vivo. Xanthohumol is already being used as a dietary supplement to encourage overall health and has shown few side effects. This fact combined with the potential anticarcinogenic activity found here warrants clinical investigation on patients with carcinoid disease.
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 951. doi:1538-7445.AM2012-951
Abstract 953: Therapeutic significance of estrogen receptor ≤ agonists in gliomas
Authors: Sareddy Gangadhara Reddy , Nair Binoj C. , Gonugunta Vijaya K. , Zhang Quan-guang , Brann Darrell W. , Tekmal Rajeshwar Rao , Vadlamudi Ratna K. 
Published: August 2012

Abstract
Purpose: Gliomas are the most common type of primary brain tumors with bleak prognosis. Gliomas exhibit gender bias with females at lower risk than males, implicating estrogen mediated protective effects. Estrogen functions are mediated by two ER subtypes: ERbeta, that functions as tumor promoter and ERbeta that function as tumor suppressor. In this study, we examined the status of ERbeta and tested whether natural ERbeta agonists have therapeutic potential on gliomas. Experimental Design: Tumor microarrays (TMAs) were utilized to determine the levels of ERbeta in gliomas. Therapeutic effect of three ERbeta agonists was determined using proliferation, foci formation and cell cycle progression assays. Functionality of ERbeta signaling in gliomas was determined by reporter assays and localization by confocal microscopy. The therapeutic potential of liquiritigenin was determined by systemic administration in a glioma xenograft model. Results: TMA analysis revealed that ERα expression is down regulated in high-grade gliomas. Glioma model cells exhibited detectable ERα with functional ERα signaling. Treatment of glioma cells with ERα agonists resulted in significant decreases in proliferation. Further, ERbeta agonist treatment induced the expression of ERα. Compared to control mice, animals treated with liquiritigenin had 50% reduction in tumor volume and size. IHC analysis of tumors revealed a significant increase in the nuclear ERα expression with a concomitant decrease in cell proliferation in the liquiritigenin-treated group. Conclusion: We found that ERα agonists promote both expression and tumor suppressive functions of ERα. Liquiritigenin, a plant-derived ERα agonist significantly reduced in vivo tumor growth in a xenograft model. Our results suggest that ERα signaling has a tumor suppressive function in gliomas and thus ERα agonists may represent a novel class of drugs for curbing glioma progression. Since ERα agonists are currently in clinical trials and are well tolerated with fewer side effects, identification of an ERα agonist as a therapeutic agent can be readily extended to clinical use with current chemotherapies, providing an additional tool for enhancing survival in glioma patients.
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 953. doi:1538-7445.AM2012-953
Abstract 955: Role of cMYC as a critical determinant of estrogen-independent growth of estrogen deprivation-resistant breast cancer cells
Authors: Sengupta Surojeet , Biarnes Michael C. , Jordan V Craig 
Published: August 2012

Abstract
Around two-third of all breast cancers express estrogen receptor alpha (ER), which depend upon estrogen for proliferation of the ER positive breast cancer cells. Aromatase inhibitors (AI) are used extensively to treat postmenopausal patients, which block the synthesis of estrogen and render an “estrogen-deprived” environment. Unfortunately, long-term treatment with AIs is associated with “AI-resistant” breast cancers, which by-passes the dependency on estrogen for the growth of the resistant breast cancer cells. To mimic these resistant breast cancers we have developed an estrogen-deprivation (ED) resistant cell line known as MCF7:5C cells from the parental ER positive MCF7 cells by propagating them in estrogen-free conditions for more than a year. MCF7:5C cells are ER positive and grow spontaneously in vitro as well as form xenograft tumors in the athymic mice in absence of estrogen (ref: Lewis et al., JNCI, 2005; 97(23):1746-59). To understand the underlying mechanism and identify the molecular determinant responsible for the estrogen-independent growth of these breast cancer cells we found that a critical estrogen-regulated gene, cMYC, is upregulated in these ED-resistant MCF7:5C cells. Basal levels of cMYC mRNA as well as the protein level were elevated three to four fold as compared to parental MCF7 cells which are dependent on estrogen for growth. Cell cycle analysis revealed twice as many “S” phase MCF7:5C cells as compared to MCF7 cells under basal condition. Treating the cells with a cMYC inhibitor, 10058-F4, decreased the number of ‘S’ phase cells and increased the cells in ‘G1′ phase in MCF7:5C cells but not in parental MCF7 cells, in a dose dependent manner. Interestingly, treatment with fulvestrant, a complete anti-estrogen, which inhibits the growth of the MCF7:5C cells by 50% also decreased the cMYC mRNA levels by similar extent. To understand the precise mechanism by which high levels of cMYC transcripts are synthesized in MCF7:5C cells we investigated the promoter of the cMYC gene and found that under basal conditions the recruitment of phosphor-serine-2-RNA polymeraseII, which is a marker of RNA elongation, was significantly higher in MCF7:5C cells as compared to the parental MCF7 cells. This study strongly indicates cMYC as a critical determinant responsible for estrogen-independent growth of ED-resistant breast cancer cells. Grant Support: This work (VCJ) was supported by the Department of Defense Breast Program under Award number W81XWH-06-1-0590 Center of Excellence; the Susan G Komen For The Cure Foundation under Award number SAC100009.
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 955. doi:1538-7445.AM2012-955
Abstract 956: The liver-X-receptor-α is involved in the induction by Tamoxifen of breast cancer cell differentiation and death
Authors: Segala Gregory , de Medina Philippe , Paillasse Michael , Jordan V. Craig , Silvente-Poirot Sandrine , Poirot Marc 
Published: August 2012

Abstract
Hormonotherapy with Tamoxifen (Tam) is one of the main strategies used world-wide for the treatment of estrogen receptor positive breast cancer. However, partial responses, tumor recurrence and acquired resistance to Tam may involve mechanisms unrelated to Estrogen Receptors (ER). Studies on non-ER related mechanisms of action of Tam led us to find that it induced breast cancer cell differentiation and death through the modulation of sterol metabolism and the stimulation of sterol oxidation (de Medina et al, Cell Death Differ, 2009), and that Tam inhibited cholesterol epoxide hydrolase (ChEH). ChEH catalyzes the trans hydration of cholesterol-5,6-epoxides (CE) and this activity is a property of the microsomal antiestrogen binding site (AEBS) (de Medina et al, PNAS, 2010). In the present study we report that Tam and AEBS ligands stimulated the oxidation of cholesterol into CE and induced the accumulation of CE in MCF-7 cells through the inhibition of ChEH at therapeutic concentrations. Since CE has been reported to be a modulator of Liver-X-Receptors (LXR), we investigated the impact of Tam and other AEBS ligands on LXR-dependent gene expression: Tam and AEBS ligands modulated the expression LXR-dependent genes in MCF-7 cells. This effect had a 24 to 48 hour lag time while the effect of direct LXR modulators was observable after 6 hours, suggesting an indirect action of AEBS ligands. The involvement of CE in the control of transcription by Tam and AEBS ligands was supported by the observation that vitamin E, which inhibited the formation and the accumulation of CE, totally blocked this transcriptional modulation. We found that knocking down LXR-α using interfering RNAs in MCF-7 cells blocked the transcriptional modulation of LXR-controlled genes induced by CE, Tam and AEBS ligands. Finally, we found that the knock down of LXR-α reproduced the vitamin E inhibition of the induction of differentiation and death of MCF-7 cells. Altogether, these data showed that LXR-α is implicated in the anticancer action of Tam and identified a new signaling pathway that could explain sensitivity and resistance to Tam.
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 956. doi:1538-7445.AM2012-956
Abstract 975: Employing functional genomics to reveal emergent dependencies
Authors: Cappell Kathryn , When Amy , Taus Patrick , Maxfield Kimberly , Whitehurst Angelique 
Published: August 2012

Abstract
Using a pangenomic loss of function strategy, our group has recently discovered that a cohort of gametogenic genes modulates chemoresponsiveness in tumor cells. Numerous studies focused on identifying aberrant gene expression patterns in tumors have previously correlated the presence of gametogenic genes with the tumorigenic state. Our functional genomics approach has now revealed that these tumor-activated aberrant gene products may play essential roles in supporting tumor cell fitness in the presence of insults, such as genotoxic stress. Specifically, depletion of each of the 8 gametogenic genes identified in our screen results in an increase in mitotic transit time and a reduction in mitotic fidelity in the presence of paclitaxel, demonstrating a requirement for their function at the level of chromosome segregation. At the cell biological level, these components contribute to mitotic spindle architecture by supporting centrosomal coalescence, centrosome duplication and/or microtubule stability. Given that the expression of these genes is otherwise biased towards the germline, they could present pharmacological entry points with an extraordinary therapeutic window. For example, we find that the CT-antigen, ACRBP, specifies poor outcome in ovarian patients and depletion of ACRBP can enhance sensitivity to paclitaxel in ovarian tumor explants in vitro and an ovarian orthtopic xenografts in vivo. In addition, we find that a small molecule that targets the gametogenic protein, TACC3, synergizes with paclitaxel to reduce tumor cell growth. We propose that the dependency on these gametogenic components may arise as a consequence of passage through a selection bottleneck, during tumor evolution, which requires acquisition of traits that normalize the mitotic perturbations originally driving the plasticity of preneoplastic genomes. We show that such traits, when defined by otherwise anomalous gene products, may represent conceptually ideal intervention targets with wide therapeutic windows.
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 975. doi:1538-7445.AM2012-975