bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1294: Identification of the binding domains that allow ligand-independent co-activation of androgen receptor by Gli2.
Authors: Li Na , Chen Mengqian , Buttyan Ralph 
Published: August 2014

Abstract
Gli proteins are transcription factors that mediate the cellular response to Hedgehog signaling. Gli activity guides cell fate decisions during development and is required for the proper morphogenesis of embryonic tissues, including the prostate gland. Previously, we showed that exogenous overexpression of Gli1 or Gli2 in androgen-deprived LNCaP cells increased the expressions of androgen-dependent genes in prostate cancer (PCa) cells and conferred androgen-independent growth behavior to them (Chen et al., Mol Cancer, 9: 89-101, 2010). We also showed that Gli1 or Gli2 proteins co-immunoprecipitate with AR, suggesting that AR interacts with Gli proteins to mediate these effects. Based upon this data, we proposed that Gli1/2 proteins are ligand-independent co-activators of AR in PCa. To better understand the Gli2-AR interaction and its effects on PCa responsiveness to androgen ablation, we fine mapped the specific interaction domains between Gli2 and AR. Complete or partial recombinant Gli2 cDNAs were tagged with GST and the GST-tagged proteins were purified on glutathione beads prior to incubation with in vitro translated human AR protein fragments. GST pulldown assays showed that GLI2 specifically recognizes and binds the Tau5 region within the AR N-terminal domain (AA 391-555). Likewise, AR binds to Gli2 within an extended
C-terminal domain (AA 628-1091) that may involve two distinct AR binding sites. AR co-activation studies in 293T cells shows that the presence of binding site(s) and the Gli2 activation domain are required for Gli2 co-activation of AR. Gli2 was tested for its ability to co-activate natural truncated variants of the AR. The interaction of Gli2 with the Tau4 domain of AR was consistent with the ability of Gli2 to co-activate truncated variants of the AR that lack the DNA binding domain.
Our work demonstrates that Gli2 co-activation of AR requires direct interaction between the tau5 domain in the AR N-terminus and the AR binding domains in the Gli2 C-terminus as well as the Gli2 activation domain. Gli2 binding at tau5 supports co-activation of the wildtype AR (in both the presence and absence of androgen) as well as co-activation of truncated receptors that do not bind androgens. As such, the evidence that Gli2 expression is increased in PCa by androgen ablation suggests that it may be a factor in progression to castration resistant PCa.
Supported by the DOD PCRP (W81XH-10-1-0493, to RB).
Citation Format: Na Li, Mengqian Chen, Ralph Buttyan. Identification of the binding domains that allow ligand-independent co-activation of androgen receptor by Gli2. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1294. doi:10.1158/1538-7445.AM2013-1294
Abstract 1297: SETD6-mediated deregulation of NF- κB signaling in 4-ABP-induced bladder carcinogenesis.
Authors: Mukherjee Neelam , Ghosh Rita 
Published: August 2014

Abstract
Epidemiological data support an etiological role for chemicals from occupational exposure and cigarette smoke with increased risk of bladder cancer. However, epigenetic effects of these chemicals remain to be elucidated. Protein methyltransferases (PMTs) methylate protein lysine and arginine residues and play an important role in regulating gene transcription. Deregulation of SET-domain-containing PMTs has a crucial role in carcinogenesis. SETD6 has been shown to monomethylate RelA (a principal subunit of NF-κB at Lys310). Monomethylated RelA recruits GLP (G9A-like protein), a histone dimethyl transferase to the NF-κB target genes, which results in transcriptional repression. The role of SETD6 in bladder cancer is unknown. We used qPCR and immunoblotting to determine changes in SETD6 at the mRNA and protein level in bladder cancer cells relative to primary urothelial cells. We also found that knockdown of SETD6 significantly decreases the viability and proliferation of bladder cancer cells suggesting that SETD6 may function as an oncogene in bladder cancer. Furthermore, we also found that message and protein levels of SETD6 are induced in primary urothelial cells following treatment of 4-aminobiphenyl (4-ABP), an important constituent of cigarette smoke. Preliminary results indicate that induction may be mediated by 4-ABP-induced ROS. RelAK310Me1 level also increased with 4-ABP treatment showing the increase in SETD6 functional activity with 4-ABP exposure. We also found the decrease in expression of RelB, one of the target genes of RelA. Overall our results show that SETD6 may function as an oncogene in 4-ABP induced bladder cancer by deregulating transactivation property of RelA. These results show for the first time the relevance of PKMTs and epigenetic regulation of NF-κB in carcinogen induced bladder cancer. Supported by RO3 CA136058 (RG).
Citation Format: Neelam Mukherjee, Rita Ghosh. SETD6-mediated deregulation of NF- κB signaling in 4-ABP-induced bladder carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1297. doi:10.1158/1538-7445.AM2013-1297
Abstract 1301: Metformin induces cytotoxicity by TP and ERCC1 decrease.
Authors: Lin Yun-Wei , Huang Yu-Ching , Tseng Sheng-Chieh , Chiu Hsien-Chun , Chen Huang-Jen , Huang Yi-Jhen , Wo Ting-Yu , Weng Shao-Hsing , Ko Jen-Chung 
Published: August 2014

Abstract
Metformin is an anti-diabetic drug recently shown to inhibit cancer cell proliferation and growth, although the involved molecular mechanisms have not been elucidated. In many cancer cells, highly expression of thymidine phosphorylase (TP) and ERCC1 are associated with poor prognosis. We used A549 and H1975 huamn non-small cell lung cancer (NSCLC) cell lines to investigate the role of TP and ERCC1 expression in metformin-induced cytotoxicity. Metformin treatment decreased cellular TP and ERCC1 protein and mRNA levels by down-regulating phosphorylated MEK1/2-ERK1/2 protein levels in a dose- and time-dependent manner. The enforced expression of the constitutively active MEK1 (MEK1-CA) vectors significantly restored cellular TP and ERCC1 protein levels and cells viability. Specific inhibition of TP and ERCC1 expression by siRNA enhanced the metformin-induced cytotoxicity and growth inhibition. In conclusion, metformin induces cytotoxicity by down-regulating TP and ERCC1 expression in NSCLC cells.
Citation Format: Yun-Wei Lin, Yu-Ching Huang, Sheng-Chieh Tseng, Hsien-Chun Chiu, Huang-Jen Chen, Yi-Jhen Huang, Ting-Yu Wo, Shao-Hsing Weng, Jen-Chung Ko. Metformin induces cytotoxicity by TP and ERCC1 decrease. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1301. doi:10.1158/1538-7445.AM2013-1301
Abstract 1302: Targeting mTORC1 by epidermal overexpression of PRAS40(T246A) suppresses TPA-induced epidermal hyperplasia during tumor promotion.
Authors: Rho Okkyung , DiGiovanni John 
Published: August 2014

Abstract
Akt activation is an important event during the early stages of skin tumor promotion by diverse tumor promoting stimuli. Transgenic mice overexpressing either wild-type Akt1 (Aktwt) or a constitutively active form of Akt1 (Aktmyr) exhibit dramatically enhanced susceptibility to two-stage skin carcinogenesis and skin tumor promotion. Several downstream Akt targets are modulated (i.e., increased phosphorylation) in keratinocytes during tumor promotion, including the mammalian target of rapamycin (mTORC1). Recent experiments show that inhibiting mTORC1 by using topical rapamycin in both wild-type and BK5.Aktwt transgenic mice can effectively block TPA-induced activation of mTORC1 signaling, epidermal hyperproliferation and skin tumor promotion in a dose-dependent manner. Treatment with rapamycin also inhibited TPA-induced proliferation and migration of labeling retaining cells (LRCs) of the bulge region from the hair follicles to upper epidermal compartments. To further examine the importance of mTORC1 signaling in epithelial carcinogenesis, we generated BK5.PRAS40mt (PRAS40T246A) mice using the BK5 vector that targets expression to the basal layer of epidermis. PRAS40 was originally identified as a novel Akt substrate with a phosphorylation site at Thr246 and acts as a negative regulator when bound to mTORC1. PRAS40T246A expressed in BK5.PRAS40mt mice remained bound to raptor even after TPA treatment as determined by immunoprecipitation analysis. BK5.PRAS40mt mice displayed reduced phosphorylation of both S6K (T389) and 4EBP1 (S65) in epidermis following treatment with TPA. Furthermore, these transgenic mice were significantly less sensitive to TPA-induced epidermal proliferation (measured by both epidermal thickness and labeling index) compared to nontransgenic siblings. TPA-mediated migration and proliferation of LRCs was also inhibited in BK5.PRAS40mt mice. BK5.PRAS40mt mice also expressed lower levels of cell cycle proteins in epidermis after TPA treatment. Collectively, the current data further support the hypothesis that downstream signaling pathways through mTORC1 contribute significantly to the process of skin tumor promotion through effects on proliferation. Supported by CA37111 and 129409.
Citation Format: Okkyung Rho, John DiGiovanni. Targeting mTORC1 by epidermal overexpression of PRAS40(T246A) suppresses TPA-induced epidermal hyperplasia during tumor promotion. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1302. doi:10.1158/1538-7445.AM2013-1302
Abstract 1303: Key roles for Gab1, phosphatidylinositol-3-kinase, COX-2, prostaglandin E2 and TGF-alpha in linoleic acid-induced upregulation of lung and breast cancer cell growth.
Authors: Kikawa Keith D. , Martins Clarissa R. , Johnson Eric D. , Beck Kristen , Mouradian Michael , Pardini Ronald S. 
Published: August 2014

Abstract
The omega-6 polyunsaturated fatty acid, linoleic acid (LA), is prevalent in Western diets and is known to enhance the tumorigenesis of mammary cancer models; with previous work demonstrating an upregulation of phosphatidylinositol-3-kinase (PI3K) signaling may play a key role. In this study, a mechanism for LA's upregulation of cancer cell growth is defined. High levels of LA in animal diets or cell culture medium initiates a series of events beginning with increased cyclooxygenase (COX) activity, which leads to increased prostaglandin E2 (PGE2) production, that subsequently increases matrix metalloproteinase (MMP) levels and transforming growth factor alpha (TGF-α). TGF-α is a classic growth factor for the epidermal growth factor receptor 1 (EGFR), which plays a role in a large number of cancers. The Grb2-associated binding protein 1 (Gab1) is a scaffolding protein that can complex with EGFR to activate PI3K signaling. Recent studies in our laboratory reveal LA supplementation of the breast cancer cell line BT-474 and the lung adenocarcinoma cell line A549 greatly increases the association between Gab1 and EGFR, while at the same time dramatically decreasing Gab1 protein levels. These changes are concomitant with increases in activated Akt (pAkt), a downstream signaling component in the PI3K signaling pathway. Moreover, inhibitors of EGFR, PI3K and Gab1-specific siRNAs are capable of reversing LA-induced upregulation of pAkt, as well as observed increases in cell proliferation for these models. These data establish Gab1 as major target in LA-induced enhancement of tumorigenesis.
Citation Format: Keith D. Kikawa, Clarissa R. Martins, Eric D. Johnson, Kristen Beck, Michael Mouradian, Ronald S. Pardini. Key roles for Gab1, phosphatidylinositol-3-kinase, COX-2, prostaglandin E2 and TGF-alpha in linoleic acid-induced upregulation of lung and breast cancer cell growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1303. doi:10.1158/1538-7445.AM2013-1303
Abstract 1304: HSF1 facilitates cell transformation by enhancing the expression of extracellular proteins.
Authors: Kuo Hsiao-Hui , Yih Ling-Huei 
Published: August 2014

Abstract
The expression level or the activity of heat shock factor-1 (HSF1), a master transcriptional regulator of the heat shock response, is elevated in cancer cell lines and tumor tissues. Loss of HSF1 function has been demonstrated to prevent oncogenesis. We thus examined whether and how HSF1 induces cell transformation using anchorage-independent growth as a surrogate for transformation phenotype. CGL2 cells overexpressing HSF1 (CGL2-wtHSF1) were more proficient to form colonies in soft agar than the parental control cells (CGL2-Neo). Cells stably depleted of HSF1 (CGL2-shHSF1), on the other hand, were unable to form colonies in soft agar. The diminished ability of CGL2-shHSF1 cells to grow in soft agar was rescued by ectopic expression of wild-type HSF1 but not an S326A substitution mutant or a C-terminal (transactivation domain) deletion mutant, indicating that phosphorylation at S326 and/or the transactivation activity of HSF1 was required for its ability to enhance anchorage-independent growth. In addition, conditioned medium collected from HSF1-overexpressing cells could induce anchorage-independent growth of HSF1-depleted cells. These results indicated that HSF1 might enhance cell transformation by transactivating the expression of particular extracellular proteins.
Citation Format: Hsiao-Hui Kuo, Ling-Huei Yih. HSF1 facilitates cell transformation by enhancing the expression of extracellular proteins. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1304. doi:10.1158/1538-7445.AM2013-1304
Abstract 1315: Regulation of Nodal expression by estrogen in hormone responsive human breast cancer cell lines.
Authors: Das Padmalaya , Quail Daniela , Postovit Lynne-Marie 
Published: August 2014

Abstract
Breast cancer is one of the most common cancers among Canadian women. Estrogen plays a key role in the in the normal growth and development of the breast and is also a major contributor to breast cancer growth. Recent studies have demonstrated that embryonic morphogen, Nodal is expressed in metastatic breast cancers and that its expression is correlated with breast cancer progression. In silico analysis of the Nodal promoter has revealed putative estrogen receptor binding sites (ERE) in proximity to the transcription start site. Our goal in this study is to investigate the role of estrogen on Nodal expression in human breast cancer cell-lines. Stimulation of MCF-7 and T47D breast cancer cell-lines that are estrogen receptor positive and express low levels of Nodal with 10nM of estradiol (E2) for varying amounts of time revealed that Nodal protein expression increases at about 48 hours after E2 exposure and persists up to 120 hours. Treatment with the E2 antagonist, ICI-182,780 (ICI) abrogates the E2-enhanced Nodal protein expression. Conversely, treating the MCF- 7 and T47D cells with recombinant Nodal resulted in a decreased expression of estrogen receptor in these cells both at the transcript and protein levels. These preliminary results suggest that there is a bidirectional interaction between estrogen receptor and Nodal in these cell-lines. Future experiments are aimed at understanding in depth this bidirectional phenomenon to provide better insight into hormonal regulation in metastatic breast cancer.
Citation Format: Padmalaya Das, Daniela Quail, Lynne-Marie Postovit. Regulation of Nodal expression by estrogen in hormone responsive human breast cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1315. doi:10.1158/1538-7445.AM2013-1315
Abstract 1319: Regulation of AR transcriptional activity and prostate cancer cellular proliferation by DACH1/Eya1/Six1 pathway.
Authors: Wang Jing , Cai Shaoxin , Chen Ke , Li Sean , Pestell Richard , Wu Kongming 
Published: August 2014

Abstract
Prostate cancer progression from androgen responsive to androgen-depletion therapy resistance is a major cause of treatment failures. Novel therapies targeting this patient are a major clinical challenge. We previously reported that the cell fate determination factor DACH1 inhibits androgen signaling though binding the AR and enhancing co-repressor recruitment in the context of local chromatin at AR responsive genes. The repression of AR function of by DACH1 was partly rescued by the co-activators p300 and SRC. The repression was enhanced by ectopic expression of HDACs. We had previously shown that DACH1 inhibited proliferation of androgen-dependent LnCAP cells. To further explore the significance of DACH1 in human prostate cancer, we established stable cell lines expressing DACH1 or its DS domain deleted mutant (ΔDS) in androgen-independent C4-2 cells and AR-negative PC-3 cells by retrovirus infection. Stable expression of DACH1 inhibited cellular proliferation in both cell lines, requiring the DS domain. Ectopic expression of DACH1 inhibited colony formation of the androgen-independent 22RV1 cells. DACH1 inhibited migration, invasion and tumor growth of AR-negative PC-3 cells. Since DACH1, Eya1 and Six1 function together as a network to control cellular differentiation and organ formation during development, we examined whether other components of RDGN pathway, could regulate androgen signaling. In hormone responsive LnCAP cells, ligand stimulation (DHT, 50nM) induced 17 folds activation of MMTV Luc, co-expression of Eya1 reduced AR transactivation, and the repression required the EYA phophatase domain. Expressions of the AR co-repressors, HDAC1, HDAC3 or SirT1 inhibited the ligand-induced AR activity. Eya1 enhanced co-repressor function at the PSA and MMTV promoters. Consistent with our previous publication, DACH1 repressed ligand-induced activity &gt;70%, Eya1 modified DACH1 repression of AR activity. Together, our studies demonstrated that the RDGN regulates both androgen dependent and independent prostate cancer cellular proliferation and tumorigenesis.
Citation Format: Jing Wang, Shaoxin Cai, Ke Chen, Sean Li, Richard Pestell, Kongming Wu. Regulation of AR transcriptional activity and prostate cancer cellular proliferation by DACH1/Eya1/Six1 pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1319. doi:10.1158/1538-7445.AM2013-1319
Abstract 132: Divergent estrogen receptor positive and negative breast cancer trends and etiologic heterogeneity in Denmark .
Authors: Anderson William F. , Rosenberg Philip , Petito Lucia , Katki Hormuzd A. , Ejlertsen Bent , Ewertz Marianne , Rasmussen Birgitte B. , Jensen Maj-Britt , Kroman Niels 
Published: August 2014

Abstract
Background: Long-term breast cancer trends in incidence in the United States (US) show rising ER positive rates and falling ER negative rates. We hypothesized that these divergent trends reflect etiologic heterogeneity and that comparable trends should be observed in other countries with similar risk factor profiles.
Methods: We analyzed invasive female breast cancers in Denmark from 1993-2010. We summarized the overall trend in age-standardized rates with the estimated annual percentage change (EAPC) statistic, and used age-period-cohort models to estimate age-specific EAPCs, cohort rate ratios (CRRs), and projections for future time periods (2011-2018).
Results: In Denmark, the overall rate of ER positive cancers rose between 1993 and 2010 by 3·0%/year (95% CI: 2·8 to 3·3%/yr) while the overall rate of ER negative cancers fell by 2·1%/year (95% CI: -2·5 to -1·6%/yr). The ER positive rate increased fastest among postmenopausal women and the ER negative rate decreased fastest among premenopausal women, reflecting that cohorts born after 1944 were at relatively higher risk of ER positive tumors and lower risk of ER negative tumors. If current trends continue, ER positive cancers will increase at least 13% and ER negative cancers will fall as much as 15% by 2018.
Conclusion: Divergent ER-specific trends are consistent with distinct etiologic pathways. If trends in known risk factors are responsible, the Danish and US experience may foreshadow a common pattern worldwide.
Citation Format: William F. Anderson, Philip Rosenberg, Lucia Petito, Hormuzd A. Katki, Bent Ejlertsen, Marianne Ewertz, Birgitte B. Rasmussen, Maj-Britt Jensen, Niels Kroman. Divergent estrogen receptor positive and negative breast cancer trends and etiologic heterogeneity in Denmark . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 132. doi:10.1158/1538-7445.AM2013-132