bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 832: MicroRNA-30c inhibits human breast tumor chemo-resistance by regulating twinfinlin-1 (TWF1) and IL-11.
Authors: Liu Huiping , Bockhorn Jessica , Dalton Rachel , Nwachukwu Chika , Huang Simo , Prat Aleix , Yee Kathy , Chang Ya-Fang , Huo Dezheng , Lu Jun , Dolan Eileen , Perou Charles M. , Olopade Olufunmilayo I. , Clarke Michael F. , Greene Geoffrey 
Published: August 2014

Abstract
Chemotherapy resistance remains a challenging problem in the clinic and the underlying molecular mechanisms are poorly characterized. We hypothesize that epithelial-to-mesenchymal transition (EMT) is involved in therapy resistance and cancer progression, but the functional link and signalling pathways need to be elucidated. Our work discovered that miR-30c, a human breast tumour prognostic marker, plays a pivotal role in chemo-resistance and apoptosis by a direct targeting of TWF1, which encodes an actin-binding protein and promotes EMT. We also identified IL-11 as a secondary target of TWF1 in the miR-30c signalling pathway. Expression of miR-30c inversely correlated with TWF1 and IL-11 levels in primary breast tumours and low IL-11 associated with relapse-free survival in breast cancer patients. Furthermore, our study demonstrates that miR-30c is transcriptionally regulated by GATA3 in breast tumours. Identification of a novel miRNA-mediated pathway that regulates chemo-resistance and apoptosis in breast cancer will facilitate the development of novel therapeutic strategies.
This study was supported in part by The University of Chicago Women's Board (J.B.) and Chicago Fellows Program (H.L.), DOD W81XWH-09-1-0331, NIH K12 CA139160-02, NCI K99 CA160638-01A1, CTSA UL1 RR024999 (H.L.), Segal Fund and Ludwig Fund (G.L.G.).
Citation Format: Huiping Liu, Jessica Bockhorn, Rachel Dalton, Chika Nwachukwu, Simo Huang, Aleix Prat, Kathy Yee, Ya-Fang Chang, Dezheng Huo, Jun Lu, Eileen Dolan, Charles M. Perou, Olufunmilayo I. Olopade, Michael F. Clarke, Geoffrey Greene. MicroRNA-30c inhibits human breast tumor chemo-resistance by regulating twinfinlin-1 (TWF1) and IL-11. [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 832. doi:10.1158/1538-7445.AM2013-832
Abstract 835: hRrp15, a ribosome RNA processing protein, has profound function on nucleoli construction, ribosome biogenesis and cell proliferation.
Authors: Dong Zhixiong , Zhu Changjun , Jiang Wei 
Published: August 2014

Abstract
Nucleolus is the sub-organelle that controls ribosome biogenesis in cells, and ribosome biogenesis is a highly regulated process that ensures cell growth (increase in biomass) coordinated with cell proliferation. In the nucleolus, ribosomal RNA precursor (47S rRNA) is initially transcribed from rDNA and then subsequently processes into 5.8S, 18S and 28S rRNAs, together with numerous ribosome proteins and nonribosomal factors, to form 60S and 40S pre-ribosomal particles before they are exported to the cytoplasm. A large body of evidence demonstrates that perturbation of rRNA synthesis, process and/or pre-ribosomal factor function impairs ribosome biogenesis and induces cell cycle arrest. This is attributed to nucleolar disruption and diffusion of ribosomal proteins, such as Rpl11 and Rpl5, into the nucleoplasm in which these ribosomal proteins bind to and inhibit MDM2 function, resulting in p53 induction and activation. In this study, we described the identification and characterization of a human protein, hRrp15, that has sequence homology with yeast pre-ribosomal factor, Rrp15p. Previous studies showed that Rrp15p is a ribosome RNA processing protein required for 60S pre-ribosomal particle formation and/or maturation in yeast. Using immunofluorescence and sucrose gradient centrifugation analyses, we demonstrated that hRrp15 was mainly localized at nucleoli in human cells. Depletion of hRrp15 expression disrupted nucleolar structure, inducing diffusion of nucleolar protein, nucleolin, in the nucleus. In contrast to Rrp15p, hRrp15 mainly associated with 60S pre-ribosomal particle but it also presented in 40S pre-ribosomal particle. Consistently, inhibition of hRrp15 expression perturbed nucleolar formation and impaired ribosomal biogenesis in both 60S and 40S pre-ribosomal subunits. In addition, depletion of hRrp15 in human non-transformed cells, RPE1, resulted in the induction of p53 and p21 proteins and cell cycle arrest at G1-G1/S whereas depletion of hRrp15 in human tumor cells, HeLa and MCF7, caused DNA damage response with detectable γ-H2AX and apoptosis. These results indicated that hRrp15 plays a critical role in regulating formation of both 60S and 40S pre-ribosomal particles, ribosome biogenesis, construction of nucleoli, cell growth and cell proliferation in human cells. Hence, hRrp15 may serve as a potential target for cancer therapy.
Citation Format: Zhixiong Dong, Changjun Zhu, Wei Jiang. hRrp15, a ribosome RNA processing protein, has profound function on nucleoli construction, ribosome biogenesis and cell proliferation. [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 835. doi:10.1158/1538-7445.AM2013-835
Abstract 838: Distinct effects of S6K homologues on breast cancer cell survival.
Authors: Sridharan Savitha , Basu Alakananda 
Published: August 2014

Abstract
The 40S ribosomal protein S6 kinase (S6K) acts downstream of the mammalian target of rapamycin (mTOR), which is an important target for cancer therapy. mTOR inhibitors are, however, of limited success, partly due to the activation of Akt caused by persistent inhibition of mTOR/p70 S6 kinase or S6K1 via a negative feedback loop. S6K exists as two homologs, S6K1 and S6K2. While both homologs are overexpressed in breast cancer, little is known about the function of S6K2. The objective of the present study is to determine whether S6K homologs perform redundant or distinct functions with respect to Akt activation and breast cancer cell survival. Silencing of S6K1 inhibited whereas knockdown of S6K2 potentiated cell death by various apoptotic stimuli, including tumor necrosis factor-alpha (TNF) and TNF-Related Apoptosis Inducing Ligand (TRAIL). In contrast to S6K1, depletion of S6K2 decreased Akt phosphorylation in MCF-7 and T47D cells. Ectopic expression of constitutively-active Akt in MCF-7 cells restored cell survival in S6K2-depleted cells. We have previously shown that activation of Akt induces downregulation of Bid via p53. Knockdown of S6K2 caused an increase in p53 and silencing of Bid blunted the ability of S6K2 deficiency to enhance TNF-induced apoptosis. Thus, our study demonstrates for the first time that the two homologs of S6K have distinct effects on Akt activation and cell survival and that S6K2 depletion enhanced cell death via the proapoptotic Bcl-2 family member Bid. Thus, targeting S6K2 may be an effective therapeutic strategy to treat cancers. (This work was supported by the grant CA71727 from the NCI).
Citation Format: Savitha Sridharan, Alakananda Basu. Distinct effects of S6K homologues on breast cancer cell survival. [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 838. doi:10.1158/1538-7445.AM2013-838
Abstract 839: An uncharacterized mechanism of cell death independent of p53 mutation status.
Authors: Morrison Bethanie L. , Russell Elisabeth , Mitala Joseph , Bernal Federico 
Published: August 2014

Abstract
Resistance to chemotherapeutic agents is often a rate-limiting event in the treatment of metastatic cancers. Mutations of TP53 or dysfunctions in the p53 pathway are known to play primary roles in the resistance to apoptosis-inducing agents. A stapled alpha-helical p53 peptide (SAH-p53) capable of disrupting the p53-HDM2 and p53-HDMX complexes and restoring p53 function has been found to induce a death response in breast, melanoma and choriocarcinoma cancer cells independent of p53 mutational status. We have recently discovered that the mechanism of death induced by SAH-p53 does not exhibit all of the characteristics of classical apoptosis, necrosis or autophagy independently. The binding of SAH-p53 to HDM2, HDMX, or a yet unidentified target results in a mechanism that leads to the intracellular aggregation of proteins and lipids that are extruded from the cell, resulting in catastrophic damage to the integrity of the cell membrane and culminating in cell death. This type of cell death involves the loss of cytoplasm, generation of phase-clear vacuole-like structures, apparent degradation of cellular membrane components, and the significant release of uniform non-vesicular cellular components. The cellular debris, while yet undefined, displays orange staining with acridine orange as well as accumulation of MitoTracker, suggesting that the debris contains hydrophobic regions. Thus far it has been established that there is a lack of any membrane blebbing, no chromatin condensation, no apoptosis signaling events or typical necrotic bubble formation after treatment with SAH-p53 in cells harboring wild-type p53, mutant p53, or null p53, suggesting an alternative mechanism of cell death. Data suggest the manifestation of early autophagy within 6 hours of SAH-p53 treatment as evidenced by LC3 accumulation, yet this phenotype is lost within 24 hours post-treatment. In addition, the pretreatment of the cells with chloroquine does not inhibit the release of debris and changes in morphology characteristic of SAH-p53 treatment, suggesting that the mechanism of death is independent of classical autophagy. We have begun to uncover the precise mechanism of cell death through the identification and validation of the transcriptional program regulated by SAH-p53 in both wild-type and mutant p53-containing cells via microarray analysis. The complete understanding and characterization of this novel mechanism may be exploited to overcome resistance to apoptosis and thus lead to a more effective way of treating chemotherapy-resistant metastatic cancers.
Citation Format: Bethanie L. Morrison, Elisabeth Russell, Joseph Mitala, Federico Bernal. An uncharacterized mechanism of cell death independent of p53 mutation status. [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 839. doi:10.1158/1538-7445.AM2013-839
Abstract 840: Caspase 2 short isoform interacts with membrane-associated cytoskeleton proteins to inhibit apoptosis.
Authors: Han Chunhua , Zhao Ran , Wani Altaf A. , Wang Qi-En 
Published: August 2014

Abstract
Caspase-2 (casp-2) is the most conserved caspase across species, and is one of the initiator caspases activated by various stimuli. The casp-2 gene produces several alternative splicing isoforms. The exclusion of exon 9 results in the dominant casp-2 long isoform (casp-2L) mRNA, while the inclusion of exon 9 leads to the inclusion of an in-frame stop codon in casp-2, resulting in a short isoform (casp-2S) mRNA. It is believed that casp-2L promotes apoptosis, whereas casp-2S inhibits apoptosis. However, the effect of casp-2S on apoptosis is still controversial, and the underlying mechanism for casp-2S-mediated apoptosis inhibition is unclear. Here, we analyzed the effects of casp-2S on DNA damage induced apoptosis by “gain-of-function” and “loss-of-function” effects in ovarian cancer cell lines. We have clearly demonstrated that over-expression of casp-2S inhibited, while knockdown of casp-2S promoted, the cisplatin-induced apoptosis in ovarian cancer cells, as revealed by the detection of PARP cleavage and Annexin V staining. To explore the mechanism for casp-2S-mediated apoptosis inhibition, we analyzed proteins interacting with casp-2S in cells by using mass spectrometry (MS) and immunoprecipitation (IP). We have identified two cytoskeleton proteins, Fodrin and α-Actinin 4, associated with casp-2S in HeLa cells and confirmed this interaction by reciprocal IP. Furthermore, we have demonstrated that casp-2S primarily resides in the cytoplasm, and inhibits DNA damage-induced cytoplasmic Fodrin cleavage independently of cellular p53 status. Given that Fodrin cleavage is critical to the apoptotic membrane blebbing, we hypothesized that casp-2S may inhibit the blebbing during apoptosis. Interestingly, immunofluorescence studies did show that over-expression of casp-2S inhibited the cisplatin-induced membrane blebbing. Taken together, our data suggest that casp-2S interacts with the membrane-associated cytoskeleton protein Fodrin, protecting it from cleavage, to affect the formation of membrane blebbing and apoptosis. (Supported by NIH grant CA151248 to QEW, and CA93413 to AAW)
Citation Format: Chunhua Han, Ran Zhao, Altaf A. Wani, Qi-En Wang. Caspase 2 short isoform interacts with membrane-associated cytoskeleton proteins to inhibit apoptosis. [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 840. doi:10.1158/1538-7445.AM2013-840
Abstract 868: HER2-targeted engineered toxin body demonstrates selective binding and cell kill of HER2-overexpressing breast cancer.
Authors: Rajagopalan Sangeetha , Willert Erin , Wirth Rachel , Null William , Liu Jen-Sing , Higgins Jack P. 
Published: August 2014

Abstract
The HER2 receptor is overexpressed in 20-30% of breast cancers. HER2 overexpression in breast cancer has been successfully targeted by both antibody and antibody-drug conjugate approaches. Trastuzumab, a humanized monoclonal antibody is approved for the treatment of HER2 positive metastatic breast cancer. More recently, trastuzumab-DM1, an antibody drug conjugate (ADC), has shown promising clinical results in patients refractory to trastuzumab. Because DM1 is a chemotherapeutic and refractory breast cancer patients have typically progressed through several rounds of chemotherapy, we were interested in developing a new ADC approach with trastuzumab that utilized a novel mechanism of action. 5G2 is an engineered toxin body comprised of the trastuzumab scFv and a modified ribosome-inhibiting protein derived from Shiga-like toxin 1 A. 5G2 has exhibited high binding affinity to HER2 protein and HER2-expressing cells. 5G2 exerts a potent HER2-specific cytotoxic effect on HER2-expressing cells, but little activity on various HER2 negative cells. These results demonstrate that 5G2 is a promising HER2-targeted therapeutic agent against breast carcinomas and is currently under further development.
Citation Format: Sangeetha Rajagopalan, Erin Willert, Rachel Wirth, William Null, Jen-Sing Liu, Jack P. Higgins. HER2-targeted engineered toxin body demonstrates selective binding and cell kill of HER2-overexpressing breast cancer. [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 868. doi:10.1158/1538-7445.AM2013-868
Abstract 900: Chemoresistance is induced by butyrate in colon cancer cells.
Authors: Lim Soo-jeong , Choi Hyeon Gyeom , Jeon Chae Kyung , Kim So Hee 
Published: August 2014

Abstract
Purpose.
Butyric acid is a short chain fatty acid produced naturally by fermentation of dietary fiber in the colonic mucosa. It is known to play an important role in preventing the initiation and the progression of colon cancer by suppressing the proliferation of cancer cells. However, some colon cancer still develops and progresses to a more malignant and chemoresistant one despite of the presence of butyric acid. The present study was undertaken to investigate a possibility of butyrate-involved mechanism by which the colon cancer cells acquire resistance to chemotherapeutic drugs.
Methods.
Human HCT116 colon cancer cells were exposed to progressively increasing concentrations of butyrate for three months to establish a colon cancer cell line with acquired resistance to butyrate. After obtaining butyrate-resistant cells, the sensitivity against multiple chemotherapeutic drugs were compared between parental and butyrate-resistant cells. The expression of proteins related to chemotherapeutic response was also compared by immunoblotting analysis.
Results.
Butyrate-resistant HCT116 cancer cell lines could be established by culturing cells in the presence of butyrate up to 0.8 mM concentration. The concentrations inhibiting the cell growth by 50% (IC50) of butyrate was 0.62 and 4.56 mM in parental and butyrate-resistant HCT116 cells. Butyrate-resistant HCT116 cells were also resistant to widely used chemotherapeutic drugs: the IC50 after paclitaxel, doxorubicin or 5-FU treatment were 2.10-, 3.98- and 1.6-fold higher in butyrateresistant cells compared with parental cells. The expression of multidrug resistance-related proteins that function as drug efflux pumps such as P-glycoprotein and the multidrug resistance-associated protein 1 were not changed at protein level. Among the apoptosis-involved proteins, the expression of anti-apoptotic BcL-2 protein was increased while that of proapoptotic BAD protein was reduced in butyrate-resistant cells, suggesting that the above chemoresistance was associated with cellular resistance to apoptosis.
Conclusion.Our data herein suggests that the colon cancer cell grown in the presence of butyric acid may acquire resistance to apoptotic cell death and thus lead to resistance to chemotherapeutic drugs.
Citation Format: Soo-jeong Lim, Hyeon Gyeom Choi, Chae Kyung Jeon, So Hee Kim. Chemoresistance is induced by butyrate in colon cancer cells. [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 900. doi:10.1158/1538-7445.AM2013-900
Abstract 901: Overexpression of inhibitors of apoptosis (IAP) family members in human breast and ovarian cancer models of non-MDR1 taxane resistance.
Authors: Duran George E. , Brozovic Anamaria , Martinez Francisco J. , Francisco E Brian , Wang Yan C. , Sikic Branimir I. 
Published: August 2014

Abstract
Four breast cancer cell lines (MCF-7, BT-549, MDA-MB-231 and T-47D) and four ovarian cancer cell lines (1A9/A2780, ES-2, MES-OV and OVCAR-3) were selected for taxane resistance by exposing cells to either docetaxel or paclitaxel in the presence of the P-glycoprotein inhibitor, PSC-833 (valspodar, 2 μM). All of these co-selected variants are MDR1/ABCB1(-), and the resistance to taxanes is not transporter-mediated. We have previously reported elevated class III β-tubulin (TUBB3), reduced BRCA1, elevated CDKN1A (p21), and altered epithelial-mesenchymal transition (EMT) genes in the majority of the non-MDR1 taxane variants. Inhibitors of apoptosis (IAP) proteins directly bind and inhibit several caspases, and may play a critical role in determining cell fate after exposure to chemotherapeutic agents. In this study, we profiled the expression of IAP proteins and found elevated content in this panel of taxane-resistant human breast and ovarian cancer cell lines. In both the paclitaxel- (TP) and docetaxel-selected (TxTP) ovarian cancer cell lines we observed significantly overexpressed cIAP1 (BIRC2), cIAP2 (BIRC3), XIAP (BIRC4), and Livin (BIRC7) relative to parental cell lines. Expression of cIAP2 was undetectable in OVCAR-3 and its taxane resistant cell lines, OVCAR-3/TP20 and OVCAR-3/TxTP5. Elevated cIAP1 and XIAP levels were detected in the human breast cancer variant BT-549/TxTP50, and Livin was overexpressed in all taxane-resistant breast cancer cell models. Survivin (BIRC5) is highly expressed in cancers and has been associated with taxane resistance via its effects on apoptosis and the cell cycle. We observed reduced Survivin content in the majority of the variants established in our laboratory except for the ovarian ES-2/TP80 cell line where we found slightly elevated expression resulting from paclitaxel selection relative to its parental control. In addition to these alterations in IAP content, we observed elevated Bcl-2 in ovarian (MES-OV/TP40 and MES-OV/TxTP50) and breast (MCF-7/TxTP50, BT-549/TxTP50, and MDA231/TxTP50) cancer cell lines at the transcript level by rt-PCR and confirmed by immunoblotting. Specific gene silencing by RNAi and treatment with small molecule inhibitors will test the functional significance of IAP alterations in these models of taxane resistance.
Citation Format: George E. Duran, Anamaria Brozovic, Francisco J. Martinez, E Brian Francisco, Yan C. Wang, Branimir I. Sikic. Overexpression of inhibitors of apoptosis (IAP) family members in human breast and ovarian cancer models of non-MDR1 taxane resistance. [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 901. doi:10.1158/1538-7445.AM2013-901
Abstract 904: TP-0413 is a dual-specific inhibitor against Jak2 and Alk2 with therapeutic potential for treating anemia of chronic disease.
Authors: Stephens Bret J. , Mollard Alexis , Meng Lingyao , Bearss David J. , Warner Steven L. 
Published: August 2014

Abstract
Anemia of chronic disease is a debilitating condition commonly found in cancer patients. Studies suggest that this syndrome is largely the result of the body's production of hepcidin, a master regulator of human iron metabolism. TP-0413 is a small molecule that targets two important components of the hepcidin pathway, Janus Kinase 2 (Jak2) and Activin A receptor, type I (Alk-2). Jak2 facilitates hepcidin function by phosphorylating ferroportin upon hepcidin binding, inducing its degradation and thus preventing iron entry into plasma. Alk2 on the other hand, is a component of the signal transduction pathway that leads to hepcidin expression. Here we report on recent efforts aimed at further characterization of TP-0413. In biochemical assays TP-0413 inhibits Jak2 and Alk2 at 3.11 nM and 70 nM, respectively (IC50). In cell culture, HepG2 cells treated with TP-0413 exhibit reduced hepcidin levels, and TP-0413 is able to inhibit BMP-2 induction of hepcidin. Furthermore, TP-0413 ameliorates hypoferremia induced by LPS treatment in mice, and modulates cytokine levels in these animals. TP-0413 shows favorable drug-like properties in pharmacokinetic models, and further studies are being undertaken to advance TP-0413 towards clinical trials.
Citation Format: Bret J. Stephens, Alexis Mollard, Lingyao Meng, David J. Bearss, Steven L. Warner. TP-0413 is a dual-specific inhibitor against Jak2 and Alk2 with therapeutic potential for treating anemia of chronic disease. [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 904. doi:10.1158/1538-7445.AM2013-904