bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 157: Lapatinib induces IL-6 expression via MAPK pathway in triple-negative breast cancer cells
Authors: Hsiao Yu-Chun , Chen Yun-Ju , Tang Chih-Hsin , Huang Wei-Chien 
Published: May 2015

Abstract
Lapatinib, the dual epidermal growth factor receptor (EGFR) and HER2 tyrosine kinase inhibitor (TKI), have been tested in triple negative breast cancer (TNBC) patients in several clinical studies. However, limited clinic benefit was observed, and the metastatic ability of TNBC cells was even unexpectedly enhanced by these anti-cancer drugs in our previous studies. In this study, we found that induction of interleukin-6 (IL-6) expression was induced in lapatinib-treated cells to contribute to their increased ability of migration. Treatment of cells with the IL-6 antibody abolished the lapatinib-induced cell migration. In response to lapatinib treatment, Raf-1, Mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinases (JNK), p38 mitogen activated protein kinase (p38 or p38-MAPK), and activator protein 1 (AP-1) signaling pathways were activated to mediated the induction of IL-6 level. Furthermore, downregulation of miR-7 was found to result in the lapatinib-induced activation of Raf-1signaling pathway and IL-6 expression. Taken together, our results indicated that lapatinib enhanced the migratory ability of TNBC by increasing IL-6 expression via the Raf-1, MAPK, JNK, p38, and AP-1 pathways.
Citation Format: Yu-Chun Hsiao, Yun-Ju Chen, Chih-Hsin Tang, Wei-Chien Huang. Lapatinib induces IL-6 expression via MAPK pathway in triple-negative breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 157. doi:10.1158/1538-7445.AM2014-157
Abstract 1573: TUSC4 functions as tumor suppressor by regulating BRCA1 stability and functions
Authors: Peng Yang , Lin Shiaw-Yih 
Published: May 2015

Abstract
Expression of the BRCA1 tumor suppressor is frequently lost in breast cancer and associated with aggressive phenotypes through as yet undetermined mechanisms. In this study, we demonstrated that the tumor suppressor TUSC4 (Tumor Suppressor Candicate 4) physically interacts with multiple DNA damage response proteins and prevent its degradation by E3 ligase ubqutination pathways. Knockdown of TUSC4 enhanced BRCA1 polyubiquitination, leading to BRCA1 protein degradation and significantly reduced the efficacy of homologous recombination repair. Notably, ectopic expression of TUSC4 effectively suppressed multiple breast cancer cells proliferation, invasion, and colony formation in vitro and tumor growth in vivo. Furthermore, TUSC4 knockdown was sufficient to transform normal mammary epithelial cells and enhance the sensitivity of cells to PARP inhibitors. Microarray analysis of TUSC4 knockdown also indicated critical changes and the global impact to cancer development. Therefore, TUSC4 acts as a bona fide tumor suppressor gene through the mechanism of regulating BRCA1 protein stability and function.
Citation Format: Yang Peng, Shiaw-Yih Lin. TUSC4 functions as tumor suppressor by regulating BRCA1 stability and functions. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1573. doi:10.1158/1538-7445.AM2014-1573
Abstract 1574: CDK5 negatively regulates Rho by phosphorylating and activating the Rho-GAP and tumor suppressor functions of DLC1
Authors: Tripathi Brajendra K. , Qian Xiaolan , Mertins Philipp , Wang Dunrui , Papageorge Alex , Carr Steven , Lowy Douglas R. 
Published: May 2015

Abstract
The tumor suppressor Deleted in Liver Cancer 1 (DLC1) is frequently down-regulated in various human cancers, including breast, prostate, liver, and non-small cell lung cancer (NSCLC). Although the tumor suppressor function of DLC1 depends on its Rho-GAP (GTPase activating protein) activity, which converts Rho from the active GTP-bound form to the inactive GDP-bound form, the mechanisms regulating this activity are poorly understood. Here we determined that CDK5, a predominantly cytoplasmic serine/threonine kinase, negatively regulates Rho-GTP in normal and transformed cells that express DLC1, and that this regulation is attributable to the ability of CDK5 to activate DLC1. We found that CDK5, phosphorylates four serine residues (S120, S205, S422, S509) in the N-terminal region of DLC1, which reduces the binding of the N-terminus to the Rho-GAP domain. The phosphorylation of these serine residues stimulate the tumor suppressor activity of DLC1 - as determined by anchorage-independent growth and tumor xenograft formation - by increasing its Rho-GAP activity and facilitating its binding of several ligands. Serine-to-alanine mutations of the 4 serines increased binding between the DLC1 N-terminus and its Rho-GAP domain, resulting in a mutant protein that lacked these activities. We infer that the N-terminus of DLC1 functions as an auto-inhibitory domain that binds the Rho-GAP domain, and that phosphorylation of the N-terminal 4 serines by CDK5 reduces this interaction, activateing the Rho-GAP and tumor suppressor activities of DLC1. Interestingly, in NSCLC, the expression of CDK5, which has numerous targets, can be associated with a poor prognosis, suggesting that its activity in NSCLC might select for down-regulation of DLC1. Consistent with this hypothesis, we found that siRNA knock-down of endogenous DLC1 in a NSCLC line greatly increased the ability of CDK5 to stimulate neoplastic growth of the line. We also found, in a publicly available tumor database, that poorly differentiated NSCLC is much more likely to express high levels of CDK5 mRNA together with low levels of DLC1 mRNA than is well differentiated NSCLC. Thus, we have identified negative Rho regulation as a new function for CDK5, found DLC1 is the key target for this regulation, elucidated a CDK5-dependent post-translational modification for activating DLC1, and demonstrated the relevance of these observations to NSCLC.
Citation Format: Brajendra K. Tripathi, Xiaolan Qian, Philipp Mertins, Dunrui Wang, Alex Papageorge, Steven Carr, Douglas R. Lowy. CDK5 negatively regulates Rho by phosphorylating and activating the Rho-GAP and tumor suppressor functions of DLC1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1574. doi:10.1158/1538-7445.AM2014-1574
Abstract 1576: Characterization of a mouse line lacking the PDZ-binding domain of PTEN
Authors: Chan Andrew M. , Guan Hong , Many Alex M. 
Published: May 2015

Abstract
PTEN encodes a phosphatase for phosphatidylinositides and serves as a key negative regulator of the phosphatidylinositol 3-kinase signaling pathway. PTEN possesses a carboxyl-terminal Postsynaptic density-95/Dlg-1/ZO-1-binding domain (PDZ-BD) implicated in membrane targeting. Since the physiological function of this domain was unclear, a mouse strain lacking this domain was generated. PtenΔPDZ/ΔPDZ mice developed normally although the haploinsufficient mice (PtenΔPDZ/-) were under represented by 50% based on Mendelian ratio of inheritance. PtenΔPDZ/- mice that survived to adulthood harbored a ∼8 % increase in brain masses when compared to PTEN heterozygous (Pten+/-) animals. However, PtenΔPDZ/- mice do not have a greater propensity in neoplastic progression of the prostate, lymph nodes, and endometrium. Independently, the Primary astrocytes from PtenΔPDZ/ΔPDZ mice displayed marginally greater Akt activation following stimulation by epidermal growth factor although both proliferative and migratory capacities were not altered. Crossing PtenΔPDZ/ΔPDZ mice with a breast cancer model, MMTV-PyMT; and a glioblastoma model, GFAP-Ha-Ras, resulted in enhanced metastasis and reduced survival, respectively. Overall, these data provide the first demonstration of a physiological relevance of PTEN PDZ-BD in embryonic development, brain size regulation and tumor progression.
Citation Format: Andrew M. Chan, Hong Guan, Alex M. Many. Characterization of a mouse line lacking the PDZ-binding domain of PTEN. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1576. doi:10.1158/1538-7445.AM2014-1576
Abstract 1580: Age-related difference in the susceptibility phthalate-induced injury in Sprague-Dawley rat
Authors: Traore Kassim 
Published: May 2015

Abstract
Di-2-ethylhexyl phthalate (DEHP), a commonly used plasticizer of synthetic polymers causes liver tumorigenesis, and both short and long-term effects on the reproductive system of male rats. Whether initial exposures to DEHP in early developmental stage affect the susceptibility to injury by subsequent exposures later in life remain unknown. Pregnant dams of Sprague Dawley rats were gavage with vehicle, 100 or 750 mg/kg bw/day of DEHP from Gestational Day 14 (GND14) until birth. After resting for twenty days, at postnatal day 21 (PND21) male offspring were gavage with vehicle, DEHP (100 or 750 mg/Kg/d) for 14 days (PND21-35). On PND35, offspring were sacrificed, serum testosterone (T) levels, body and organ (testis, liver and kidney) weight were examined. The data reveals that DEHP 750 mg/Kg/d but not 100mg/Kg/d treatment were sufficient to cause damage to testis when exposures occurs during either gestational or peripubertal (PND21-35) period. Interestingly, our data also indicated that subsequent exposures to DEHP (100 mg/Kg/day) in utero and at peri-pubertal stage were also effective to causing significant injury to testis. The serum T levels were reduced in all DEHP treatment groups. Next, we investigated the effects of peripubertal exposure to DEHP on the susceptibility to injury by subsequent exposure during adulthood. PND21 rats were subjected to oral administration of Oil, DEHP (100mg/kg/day or 750mg/kg/day) for 14 days (PND21-35). The rats were allowed to rest for 25 days until PND60. At PND60, rats were divided into groups and subsequently exposed to oil or DEHP (100 or 750 mg/Kg/d) for 14days (PND60-74). At PND74 the rats were sacrificed, serum T levels, body and organ weights were determined. Interestingly, no significant injury was observed in any of the treatment groups. Instead, and enhanced serum T levels were observed in DEHP-treated adult rats compared to control. Together, this study shows that the susceptibility to injuries following subsequent DEHP exposure is age-dependent, with immature male rats more susceptible while adults are resistant. In addition, the data also indicated that injuries sustained during peri-pubertal exposure are at least in part reversible. This work was supported by NIH-NIGMS-SCORE 2 grant SC2GM099578.
Citation Format: Kassim Traore. Age-related difference in the susceptibility phthalate-induced injury in Sprague-Dawley rat. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1580. doi:10.1158/1538-7445.AM2014-1580
Abstract 1581: Ethanol overrides DNA synthesis inhibition in response to PAHs (tobacco smoke carcinogens): a mechanistic explanation
Authors: Mukherjee Jagat J. , Kumar Subodh 
Published: May 2015

Abstract
It is a well-established fact that alcohol intake with smoking presents a potential health risk to human. Mechanistic understanding in this regard is not clear. We previously reported that DNA damage by tobacco smoke carcinogens polynuclear aromatic hydrocarbons (PAHs) is responded by cells through induction of cell growth inhibition in different cell lines. Here we observed that ethanol (EtOH) treatment at physiologically relevant concentration (60 mM) increases DNA synthesis in DNA damaging carcinogen (BPDE) treated cells. BPDE treatment of cells elicits G1-S cell cycle arrest, but EtOH does not have any significant modulating effect on G1-S arrest indicating increased DNA synthesis by EtOH is due to modulation of some other signaling event(s). EtOH co-treatment/pretreatment is unable to modulate BPDE-induced p53 accumulation and p53 phosphorylation at ser15 and ser20 indicating increased DNA synthesis by EtOH is p53 independent. We also observed that EtOH co-treatment/pretreatment potentiates BPDE-induced phosphorylation and activation of ERKs only and not p38 MAPK. Interestingly, treatment of cells with MEK1 inhibitor (PD098059) significantly reduced ethanol's ability to increase DNA synthesis in BPDE treated cells. This finding indicates that the ability of EtOH to potentiate BPDE-induced ERK activation may potentiate PAH-induced tumorigenesis.
Note: This abstract was not presented at the meeting.
Citation Format: Jagat J. Mukherjee, Subodh Kumar. Ethanol overrides DNA synthesis inhibition in response to PAHs (tobacco smoke carcinogens): a mechanistic explanation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1581. doi:10.1158/1538-7445.AM2014-1581
Abstract 1586: Toxicity screening, apoptosis hallmark events and nitro reduction of novel quinolinium salts (BQS) on lymphoma cells
Authors: Rios-Rodriguez Karoline , Soto Jessica , Velez Christian , Cox Osvaldo , Rivera Juan P. , Zayas Beatriz 
Published: May 2015

Abstract
The main purpose of this research was to evaluate the effects of two novel benzazolo[3,2-a]quinolinium salts (ABQ-48 and NBQ48) on lymphoma cells (TOLEDO). The cationic nature of these BQS can facilitate its interaction with cell organelles such as mitochondria and DNA. To determine its potential cytotoxic effects the compounds were screened through the NCI 60 cell line protocol which determines the cell viability inhibitory activity in various cancer histological types. The IC50 dose for these compounds was determined and used to assess their apoptosis induction capacity evaluating apoptosis hallmark events such as DNA Fragmentation, Caspase 3&7 activators and mitochondrial membrane permeabilization. Additionally cell reduction potential of the compounds was measured. Results from the NCI 60 cell line protocol demonstrated the toxicity of BQS in multiple cancer types including breast and colon cancer cells. Preliminary results indicated mitochondrial membrane permeabilization on cells treated with NBQ48 (51.3%) and ABQ48 (57.67%) comparable to the positive controls camptothecin (51.6%) and valinomycin (55.3%). Treated cells also presented DNA fragmentation with NBQ48 and ABQ48 (28%) comparable to the positive control 37%. Preliminary data for caspases 3&7 activation strongly suggest an intrinsic apoptosis pathway. Analysis of the reduction of nitro substituted compound NBQ 48 to the amino substituted ABQ 48 on treated cells was determined by measuring an increment on fluorescence emission, characteristic of an amino specie. In conclusion, the study provides evidence of the induction of key apoptotic events as part of the mechanism of action of these novel BQS.
Citation Format: Karoline Rios-Rodriguez, Jessica Soto, Christian Velez, Osvaldo Cox, Juan P. Rivera, Beatriz Zayas. Toxicity screening, apoptosis hallmark events and nitro reduction of novel quinolinium salts (BQS) on lymphoma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1586. doi:10.1158/1538-7445.AM2014-1586
Abstract 1590: Expression and function of Sirt6 in muscle invasive bladder cancer
Authors: Wu Minghui , Dickinson Shohreh , Zhang Jingsong 
Published: May 2015

Abstract
Unlike most other solid tumors, there is limited success of targeted agents in treating metastatic bladder cancer (BC), a lethal disease with a median overall survival of merely 13-15 months. No prevalent “drugable” driver mutations have been identified in muscle invasive bladder cancer (MIBC) so far. Several high profile publications in the past few years have put Sirt6, a member of the class III histone deacetylase in the center stage of cancer metabolism and DNA repair. We therefore assessed the expression and function of Sirt6 in MIBC. Inconsistent with its proposed function as a tumor suppressor in colon cancer, the gene expression datasets available in Oncomine did not reveal significant differences in Sirt6 mRNA levels among normal urothelium, superficial BC and MIBC. Compared to normal urothelium, carcinoma in situ, superficial BC, the median Sirt6 mRNA was the lowest in MIBC in the Dyrkjot bladder 3 dataset, but this was not statistically significant. We then studied Sirt6 protein expression with immunohistochemistry (IHC) in commercial tissue microarray as well as radical cystoprostatectomy samples in our total cancer care tumor bank. Sirt6 IHC were reviewed by pathologist and considered positive for Sirt6 if more than 5% of the tumor cells had at least 1+ Sirt6 nuclear staining. Positive Sirt6 IHC was detected in 33/56 (59%) of T2 (grade 1-3), 2/23 T3 (9%) and 0/3 T4 urothelial carcinoma. All the grade 3/high grade T3 urothelial carcinomas were negative for Sirt6 IHC. Negative Sirt6 IHC was also noted in 2 adenocarcinomas, 1 sarcomatoid carcinoma and 1 small cell MIBC. 1/18 (5%) lymph node metastasis had positive Sirt6 IHC. Consistent with its role of inhibiting aerobic glycolysis, bladder cancer cell lines with higher Srit6 have lower glucose uptake and lower lactate production. Knocking down Sirt6 expression in bladder cancer cell lines, however, did not sensitize bladder cancer lines to drug induced DNA damage. Among MIBC, much higher frequency of Sirt6 IHC positivity was noted in T2 urothelial carcinoma than T3, T4 and non-urothelial carcinomas. Data with bladder cancer cell lines suggest the function of Sirt6 in bladder cancer is primarily inhibiting aerobic glycolysis.
Citation Format: Minghui Wu, Shohreh Dickinson, Jingsong Zhang. Expression and function of Sirt6 in muscle invasive bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1590. doi:10.1158/1538-7445.AM2014-1590
Abstract 1596: CXCL13 as a mediator of oncogenic PKCϵ in prostate cancer
Authors: Garg Rachana , Abba Martin , Kazanietz Marcelo G. 
Published: May 2015

Abstract
Protein kinase C epsilon (PKCϵ), a member of the PKC family of phorbol ester/diacylglycerol receptors, has emerged as an oncogenic kinase and plays important role in cell survival, mitogenesis and invasion. PKCϵ is up-regulated in most epithelial cancers, including prostate cancer. We recently showed that transgenic PKCϵ overexpression in the mouse prostate under the control of probasin (PB) promoter leads to hyperplasia and prostatic intraepithelial neoplastic lesions but is insufficient to drive neoplastic changes. Strikingly, when we intercrossed the prostate-specific PKCϵ transgenic mice with mice haploinsufficient for Pten, a common genetic alteration in human prostate cancer, the resulting compound mutant mice (PB-PKCϵ;Pten+/- mice) developed fully invasive adenocarcinoma (unpublished observation). In the present study, to explore the mechanistic aspects of the observed cooperativity between PKCϵ overexpression and Pten deficiency, we stably overexpressed PKCϵ in mouse prostate epithelial lines that are either heterozygous (P8) or homozygous (CaP8) for Pten deletion. PKCϵ overexpression led to significant enhancement in cell proliferation as well as enhanced the levels of phospho-Akt, phospho-Erk and phospho-mTOR; these effects are more pronounced in CaP8 cells. Moreover, migration, invasion, clonogenic and soft agar colony formation assays revealed a striking synergism between PKCϵ overexpression and Pten loss. Furthermore, analysis of global gene expression by microarray revealed significant changes in gene related to EMT, adhesion, metabolism, and invasiveness following PKCϵ overexpression, Pten loss or both. In particular, a chemokine CXCL13 was found to be majorly up-regulated in CaP8-PKCϵ cells. Measurement of CXCL13 mRNA by qPCR or CXCL13 release to the conditioned medium (CM) by ELISA showed increased levels in PKCϵ overexpressing or Pten depleted cells, and these effects were synergistically enhanced in CaP8-PKCϵ cells. Remarkably, CM from CaP8-PKCϵ cells led to significant induction in growth and motility of P8 cells. Importantly, CXCL13 RNAi depletion reduced the proliferative and migratory capacity of CaP8-PKCϵ cells, thereby establishing the potential relevance of CXCL13 in the phenotypic effects of PKCϵ overexpression and Pten loss. Concurrently, the growth and motile activity of P8 cells were enhanced in response to exogenously added CXCL13. Overall, our results argue for the role of CXCL13 in mediating effects of oncogenic PKCϵ in prostate cancer.
Citation Format: Rachana Garg, Martin Abba, Marcelo G. Kazanietz. CXCL13 as a mediator of oncogenic PKCϵ in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1596. doi:10.1158/1538-7445.AM2014-1596