bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1316: Overactivation of AKT promotes hormone-independent mammary tumors
Authors: Riggio Marina , Polo Laura , Blaustein Matias , Colman-Lerner Alejandro , Lanari Claudia , Novaro Virginia 
Published: June 2012

Abstract
Using a mouse mammary tumor model induced by medroxyprogesterone acetate (MPA) that transits through different stages of hormone dependence, we have previously reported that the activation of the PI3K/AKT pathway is critical for the growth of hormone-independent (HI) mammary tumors, but not for the growth of a hormone-dependent (HD) tumor variant.
The main aim of this work was to explore whether the activation of the PI3K/AKT pathway per se is responsible for the transition from a HD to a HI tumor phenotype. To answer this question we infected primary cultures of epithelial cells obtained from HD tumors with a retrovirus that directs the expression of a constitutively active form of AKT1 (myristoylated AKT1, myrAKT1), or with the empty vector as control. We inoculated 103 cells in nude mice (n = 6). MyrAKT1 expressing HD-derived cells were able to form mammary tumors even in the absence of MPA, that is, they behaved as HI cells. These tumors were highly differentiated and displayed a ductal phenotype with a pattern of expression of cytokeratin 8 and laminin-1 typical of HI tumors. Ligand-independent phosphorylation of progesterone receptor (PR) in Ser 190 was also increased in myrAKT1 tumors supporting our hypothesis that overactivation of AKT is directly involved in the acquisition of hormone independence. Furthermore, comparing myrAKT tumors with uninfected HD tumors revealed that overactivation of AKT did not increase the incidence of lung metastasis, indicating that AKT1 is involved specifically with tumor differentiation and growth rather than with tumor cell invasiveness.
In vitro, primary cultures of mammary tumor cells modified to express myrAKT1 showed similar levels of proliferation determined by Ki67 and H3-tymidine incorporation as compared to control (cells infected with the empty vector), suggesting that the in vivo tumorigenic effect of myrAKT1 cells described above might require cell-cell or cell-matrix interactions absent in vitro. Interestingly, we found that conditioned medium from myrAKT1 tumor cells increase endogenous AKT1 activity when tested in untransfected cells. Moreover, conditioned medium from HI carcinoma associated fibroblasts (CAF-HI) increased the level of activation of the PI3K/AKT pathway in epithelial cells. Altogether, these results indicate that paracrine signals derived from the tumor cells and/or its microenvironment participate in the activation of the PI3K/AKT pathway, ultimately leading to tissue differentiation and ligand-independent mammary tumor growth. Thus, the PI3K/AKT pathway might be a key therapeutic target to prevent progression to autonomous and endocrine resistant breast 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 1316. doi:10.1158/1538-7445.AM2011-1316
Abstract 132: miR-133a as a tumor suppressive microRNA targeting multiple oncogenes in head neck squamous cell carcinoma
Authors: Nohata Nijiro , Hanazawa Toyoyuki , Kikkawa Naoko , Mutallip Muradil , Fuse Miki , Chiyomaru Takeshi , Kawakami Kazumori , Enokida Hideki , Nakagawa Masayuki , Okamato Yoshitaka , Seki Naohiko 
Published: June 2012

Abstract
Head and neck squamous cell carcinomas (HNSCC) represent 6% of all cancers. Despite of considerable advances in surgery, radiotherapy and chemotherapy, the overall 5-year survival rate for patients is less than 40% in advanced stage. The understanding of the new molecular pathways of HNSCC carcinogenesis would be helpful in improving diagnosis and therapy of the disease.
MicroRNA(miRNA) are endogenous short non-coding RNA molecules, which regulate gene expression by repressing translation or cleaving RNA transcripts in a sequence-specific manner. Growing evidence suggests that miRNAs are aberrantly expressed in many human cancers, and that they play significant roles in carcinogenesis and cancer progression. Bioinformatic prediction indicates that miRNAs regulate more than 30% of the protein coding genes. The study of the tumor suppressive miRNAs and their target genes search is important for understanding of the HNSCC carcinogenesis.
Based on our miRNA expression signature of HNSCC, miR-133a is one of the down-regulated miRNA and this finding suggests that miR-133a is a candidate of tumor suppressor. Gain-of-function analysis revealed that miR-133a transfectant inhibited cell proliferation and cell invasion in cancer cells. For target genes search of miR-133a in cancer cells, we performed genome-wide protein coding expression analysis. Among the expression study, several candidate genes were identified, such as, fascin homolog 1 (FSCN1), glutathione S-transferase P1 (GSTP1) and caveolin-1 (CAV1). Silencing of these genes showed that significant inhibition of cell growth and invasion were demonstrated in HNSCC cancer cells.
Tumor suppressive miR-133a and its target oncogenes may provide new insights into the mechanisms in cancer. Our findings have therapeutic implications and may be exploited for future HNSCC treatments.
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 132. doi:10.1158/1538-7445.AM2011-132
Abstract 1321: Estrogen-like effects of cadmium in male mice and the involvement of MAPKs pathway
Authors: Ali Imran , Penttinen-Damdimopoulou Pauliina E. , Mäkelä Sari I. , Berglund Marika , Stenius Ulla , Adamsson Annika , Åkesson Agneta , Håkansson Helen , Halldin Krister 
Published: June 2012

Abstract
Cadmium is a ubiquitous toxicant of environmental concern, classified as a category 1 human carcinogen. Clear estrogen-like effects of cadmium have been reported in ovariectomized rats after a single dose. Recent epidemiological findings might suggest increased risk of hormone-related cancers such as cancer of the endometrium and breast. However, the specific molecular mechanism of action is unknown. Recently, we have shown that estrogen-like effects of cadmium in female mice do not appear to be mediated via the classical estrogen receptor transcriptional pathway. However, some estrogen like effects, possibly mediated via the non-classical estrogen signaling pathway were observed. The aim of the present study was to investigate the estrogen-like effects of cadmium in male mice. ERE-luc male mice were injected subcutaneously with CdCl2 at 0.5, 5, 50 or 500 µg/kg b.w. or with 17α-ethinylestradiol (EE2) on three consecutive days. Testicular weights and histology, body and organ weight, Cd-tissue retention, activation of MAPK pathways and ERE dependent luciferase expression were investigated. Body weight and relative liver and kidney weights were not altered in any of the CdCl2 or EE2 treated animals as compared to the control. Relative testis weights were significantly decreased in 0.5 and 50µg CdCl2/kg b.w. treated animals as compared to control. Testicular histology analysis showed no significant changes in the tubulus diameter and epithelial thickness at stage VII, however some apoptotic cells were observed in mice treated with CdCl2. No significant alterations in ERE mediated luciferase activity were detected in any of the CdCl2 treated groups. Phosphorylation of Mdm2 was significantly increased at relatively low-dose of CdCl2 (5µg/kg b.w.), whereas no significant changes in phosphorylation of Akt were observed in CdCl2 or EE2 treated animals. Phosphorylation of Erk was found to be significantly increased after exposure to 0.5, 5 and 50µg of CdCl2/kg b.w. as compared to control. Gene expression of c-myc, c-fos, c-jun and p53 appeared to be decreased at relatively low dose of CdCl2 (5µg/kg b.w). No significant changes were observed in the expression of HSP32, p38, SP1 or ER-alpha after CdCl2 exposure. In conclusion the results suggest the involvement of MAPKs signaling pathways in cadmium induced effects in vivo after short term exposure at the doses investigated.
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 1321. doi:10.1158/1538-7445.AM2011-1321
Abstract 1331: Green tea catechin suppression of carcinogenesis and cell proliferation induced by environmental carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene
Authors: Rathore Kusum , Wang Hwa-Chain R. 
Published: June 2012

Abstract
In this study we aim to identify the role of green tea catechins (GTCs) in early prevention of breast cell carcinogenesis induced chronically by environmental carcinogens. Most sporadic breast cancers are attributable to long-term exposure to environmental factors through a multi-year, multi-step, and multi-path disease process involving cumulative genetic and epigenetic alterations in progressive breast cell carcinogenesis. Epidemiologic and experimental studies have shown that GTCs may intervene with breast cancer development. However, the mechanisms for GTC prevention of cellular carcinogenesis induced by chronic exposure to environmental carcinogens remain to be elucidated. To study the activity of GTC components in suppression of cellular carcinogenesis, we used our cellular carcinogenesis model that mimics chronic breast cell carcinogenesis induced by cumulative exposures to low doses of the environmental carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P). We detected that the four major GTC components epicatechin (EC), epicatechin-3-gallate (ECG), epigallocatechin (EGC), and epigallocatechin-3-gallate (EGCG) at non-cytotoxic levels were able to suppress NNK- and B[a]P-induced cellular carcinogenesis, as measured by suppression of the acquired cancer-associated properties of reduced dependence on growth factors, anchorage-independent growth, and increased cell mobility. We also detected that ECG was more effective than EC, EGC, and EGCG in suppression of cellular carcinogenesis. Investigating the mechanisms for GTCs in counteracting carcinogenic activity of NNK and B[a]P, we detected that all the catechins were able to suppress carcinogen-induced reactive oxygen species (ROS), resulting in suppressing ROS-induced ERK pathway activation, cell proliferation, DNA damage, and p53 expression. Our cellular model provided a new platform to identify dietary components, at non-cytotoxic levels, capable of effectively intervening in chronic breast cell carcinogenesis induced by cumulative exposures to low doses of environmental carcinogens.
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 1331. doi:10.1158/1538-7445.AM2011-1331
Abstract 1339: Upregulation of the glutathione detoxification pathway protects against cytotoxicity induced by the alkylating agent, 2-chloroethyl ethyl sulfide (CEES)
Authors: Abel Erika L. , McIvor Elizabeth , Bubel Jennifer D. , Simper Melissa S. , Powell Leslie , Fields Tammy Y. , Andreeff Michael , MacLeod Michael C. , DiGiovanni John 
Published: June 2012

Abstract
Sulfur mustard (SM) is a vesicating agent that was first used in chemical warfare over 100 years ago. SM alkylates DNA and is mutagenic in various model systems. Epidemiological studies indicate that chronic exposure increases the risk of cancer in exposed tissues. Due to its incapacitating effects, and the relative ease with which it may be synthesized, mustard gas remains a potential chemical threat to the present day. Currently, there are no antidotes for SM-induced toxicity; therefore, chemopreventive and therapeutic measures are needed. Glutathione (GSH) exerts a protective effect against SM toxicity, and detoxification of SM is believed to occur, in part, via GSH conjugation. The rate-limiting step in GSH synthesis is catalyzed by the glutamate cysteine ligase (GCL) holoenzyme, which is composed of a catalytic and a regulatory subunit (GCLC and GCLM, respectively). Cancer chemopreventive agents are known to modulate expression of GCL and GSH S-transferases (GSTs) via activation of the transcription factor, Nrf2, and may, therefore, have utility in inhibiting SM-induced damage in the skin. We have screened 6 chemopreventive agents for ability to induce GSH synthesis and protect cultured NCTC2544 human keratinocytes against the SM analogue, 2-chloroethyl ethyl sulfide (CEES). We found that sulforaphane and methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) stimulated nuclear localization of Nrf2 and induced expression of GCLM. Additionally, we found that treatment with CDDO-Me elevated reduced GSH content of NCTC2544 cells (118.0±11.6 nmol/mg protein versus 66.5±7.9 nmol/mg protein) and preserved their viability by ∼3-fold following exposure to CEES. CDDO-Me acted additively with 2,6-dithiopurine (DTP), a nucleophilic scavenging agent, to increase the viability of keratinocytes exposed to CEES by 6-fold (60% in cells treated with a combination of CDDO-Me and DTP vs 10% in cells treated with vehicle only). In vivo, topical application of either sulforaphane or CDDO-Me elevated epidermal GSH and GST levels in the skin of C57BL/6 mice. These results suggest that CDDO-Me and sulforaphane are promising chemopreventive agents for SM toxicity in the skin.
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 1339. doi:10.1158/1538-7445.AM2011-1339
Abstract 1343: Protective effect of catechol-O-methyltransferase in human renal cell carcinogenesis
Authors: Chang Inik , Liu Jan , Majid Shahana , Saini Sharanjot , Zaman Mohd S. , Chen Yi , Singh Kamaldeep , Shahryari Varahram , Sandhu Herman , Yamamura Soichiro , Dahiya Angela V. , Deng Guoren , Tanaka Yuichiro 
Published: June 2012

Abstract
Exposure to carcinogenic catechol estrogens plays a role in the development of kidney cancer. Catechol-O-methyltransferase (COMT) neutralizes the genotoxic effects of these compounds by methoxylation. Although reduced activity of COMT has been suggested as a risk factor for estrogen-associated cancers, its critical role in kidney cancer and underlying mechanisms of renal cell carcinogenesis are largely unknown. To address the role and function of COMT in renal cell carcinomas (RCC), we initially determined levels of COMT in normal kidney and clear cell RCC. The expression of COMT mRNA was down-regulated in clear cell RCC tissues as determined by quantitative PCR. Low expression of COMT protein in clear cell RCC tissues was also confirmed by immunohistochemical counting of staining score (2.5 vs. 0.5 in normal kidney and clear cell RCC, respectively, p&lt;0.001). Since COMT expression is reduced in clear cell RCC compared to normal cells, we explored the function of COMT by transiently over-expressing it in the Caki-1 clear cell RCC cell line with low levels of COMT compared to HK-2 normal renal cells. A significant increase of COMT expression in Caki-1 cells (Caki-1/COMT) compared to parent cells transfected with vector control (Caki-1/pCMV6) was confirmed by both quantitative PCR and Western blot. We investigated the role of COMT on cell proliferation and found that proliferation of Caki-1/COMT cells was decreased by 8 to 15 % in a time dependent manner (from 24 hours to 72 hours, p&lt;0.05). We also assessed the effect of COMT on cell cycle progression by flow cytometry. Over-expression of COMT led to an increase (8 ± 1.6%) in the G0/G1 phase population, whereas the number of cells in S-phase decreased from 5.5 % to 2.6 % (p&lt;0.05). These data indicate that COMT over-expression ameliorate the proliferation of Caki-1 renal cancer cell line by G0/G1 phase arrest. In addition, we analyzed whether COMT expression affects apoptosis of Caki-1 cells by flow cytometry using annexin V-FITC/7-AAD (7-amino actinomycin D) dye. COMT expression resulted in a higher percentage of cells undergoing both early and late apoptosis compared to vector controls (2.3% vs. 0.4 %, respectively for early apoptosis, and 5.5 % vs. 0.8 %, respectively for late apoptosis, p&lt;0.05). Our study indicates that COMT plays a protective role in renal cell carcinogenesis by preventing cellular proliferation and enhancing apoptosis of RCC 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 1343. doi:10.1158/1538-7445.AM2011-1343
Abstract 1345: Bioactivation of luteolin as a prodrug by tyrosinase inhibits human glutathione S-transferase and induces toxicity in SK-MEL-28 melanoma cells
Authors: Balyan Rajiv , Kudugunti Shashi , Vad Nikhil , Moridani Majid 
Published: June 2012

Abstract
Glutathione S-transferase (GST) play significant role in the metabolism and detoxification of drugs used in treatment of melanoma, resulting in a decrease in their efficacy against melanoma. In the present study, we investigated: i) the selective inhibition of GST by luteolin in the presence of tyrosinase, an abundant enzyme found in melanoma, and ii) the induction of apoptosis, change in mitochondrial permeability, cell viability, cell migration and GSH depletion by luteolin in human melanoma SK-MEL-28 cell culture. The inhibition of GST was investigated using CDNB method. DTNB method was used to measure GSH depletion. MTT assay, Annexin V apoptosis assay and TMRM fluorescence were used in the investigation of biochemical mechanism of luteolin toxicity in melanoma cells. Luteolin (40 µM) induced toxicity and death in 50% of cells after 48 h incubation. Cell treatment with luteolin (40 µM) resulted in apoptotic cell death in 70% of cells and caused 45% decrease in TMRM fluorescence indicating change in mitochondrial membrane permeability. At 1 h incubation, luteolin was bioactivated by tyrosinase to luteoline-quinone for 71% as measured by GSH depletion. The luteolin is effective in preventing metastasis of cancerous cells as evident by cell migration assay. At 48 h incubation, luteolin as low as 5 µM effectively prevented the cell migration. In the presence of tyrosinase, luteolin (10 µM) showed about 87% GST inhibition; whereas in the absence of tyrosinase, luteolin led to negligible GST inhibition. Both luteolin-SG conjugate and luteolin-quinone (10 µM) inhibited ≥90% of GST activity via reversible and irreversible competitive mechanisms with Ki of 0.9 and 6.4 µM with respect to GSH, respectively. The luteolin-SG conjugate inhibited GST activity reversibly and non-competitively with Ki of 1.8, whereas luteolin-quinone showed irreversible competitive inhibition of GST activity with Ki of 1.0 µM with respect to CDNB. While luteolin is not a substrate for GST, Luteolin (25 µM) non-competitively inhibited GST with Ki of 39 µM with respect to GSH and competitively with Ki of 61 µM with respect to CDNB. Luteolin, at the concentration range of 5-80 µM, exhibited 78-99% GST inhibition in human SK-MEL-28 cell homogenate. In summary, our results suggest that luteolin was bioactivated by tyrosinase to form a quinone and luteolin-glutathione conjugate, which played major role in the inhibition of GST. For the first time, we demonstrate that luteolin acts as a selective inhibitor of GST in the presence of tyrosinase.
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 1345. doi:10.1158/1538-7445.AM2011-1345
Abstract 136: hsa-miR-20a promotes tumorigenesis in ccRCC cancer cell lines
Authors: Kurisetty Vittal , Kovacs Krisztina , Luongo Tony , Merchan Jaime 
Published: June 2012

Abstract
Objective & Background: We have previously reported specific microRNA profiles in renal cell cancer (RCC) cell lines in vitro (Kurisetty et al. AACR Annual Meeting 2010. A # 3045;). Among the miR signatures identified, miR-20a, a member of 17-92 Oncomir cluster, stood out as a highly upregulated miR in most RCC cell lines, regardless of their VHL status. The objectives of this study are to characterize the biological significance of miR 20A upregulation in RCC. Methods: ccRCC cell lines 786.O, ACHN and KV6 and HREC, were used for cell based biological/phenotypic assays. miRNA-gene target prediction analysis was performed using miRGEN and DIANA lab programs. miR-20a-Mimic (Mi) and miR-20a-Inhibitor (In) were transiently transfected into normal HREC cell line and RCC cell lines, respectively. Cell adhesion, proliferation, softagar colony formation and transwell invasion/migration assays were performed to investigate the influences of miR-20a-Mi/In transfected into normal and ccRCC cell lines. Conditioned medium from transfected cell lines was tested for its ability to induce in vitro angiogenesis in HUVECs. Western blotting was performed to identify the changes in E2F5 protein expression in the miR-20a-Mi/In transfected normal and ccRCC cell lines. Results: In normal HREC cells, upregulation of miR 20a (by miR-20a-Mi), significantly induced cell proliferation, adhesion, migration & invasion and soft agar colony formation. miR-20a knock down in RCC cells (by miR-20a-In) significantly reduced cell proliferation, adhesion, migration & invasion and colony formation to levels similar to non-malignant HREC cells. Prediction analyses through bioinformatics approaches identified E2F5, a transcription factor and a tumor suppressor of the E2F family of transcription factors, as a target of miR-20a. Compared to non-tumor HREC cells, E2F5 was significantly downregulated in RCC cell lines, and miR-20a inhibition enhanced E2F5 expression in cancer cells. miR-20a-Mi enhanced the ability of HREC conditioned medium to induce capillary formation in HUVECs. Conclusion: Our results suggest that miR-20a may promote the tumorigenic properties of RCC in vitro. Moreover, miR 20a may promote angiogenesis. We demonstrated that E2F5 is a target of miR 20a, is reduced in RCC cell lines, and its expression is enhanced by mir-20a inhibition, suggesting that E2F5 may mediate the tumor promoting effects of miR 20a. Molecular mechanisms of miR-20a function are currently being investigated further to understand its tumorigenic potential.
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 136. doi:10.1158/1538-7445.AM2011-136