bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4178: Tcl1 enhances keratinocytes’ survival/proliferation by promoting erk and jnk/sap phosphorylation at the expense of p38 and by controlling c-fos expression through miR-29b and miR-181a-1
Authors: Bresin Antonella , Narducci Maria Grazia , Picchio Cristina , Cristofoletti Cristina , Citterich Mauro Helmer , Caprini Elisabetta , Tocco Valeria , Lazzeri Cristina , Russo Giandomenico , Ragone Gianluca 
Published: August 2012

Abstract
The Tcl1 oncogene has been initially isolated for its involvement in chromosomal translocations of T-prolymphocytic leukemias and overexpression in B chronic lymphocytic leukemia by enhancing AKT nuclear translocation and allowing the Ser-473 transphosphorylation. Tcl1, also, acts as AP-1 transcriptional inhibitor, by interacting with c-fos and c-jun. More recent works have associated Tcl1 to proliferation and self-renewal ability of ES cells under the direct activation of OCT3/4, Zfx, KLF5 transcription factors, being Tcl1 expressed in preimplantation embryos where it allows the progression beyond the 4-cells stage. We have recently shown that the Tcl1 oncogene is expressed in epidermis and defines secondary hair germ (transient-amplifying, TA) cells differentiation at catagen-telogen (the degenerative-resting phase of the hair follicle (HF)) transition, allowing the proliferation of TA cells in anagen (regenerative phase of the HF), giving the slow-cycling stem cells, the ability to incorporate BrdU. In fact, Tcl1 mutant (Tcl1-/-) affects stem-cell marker CD34 expression and BrdU incorporation in the bulge and TA cells, resulting in skin defects in adults with the onset of alopecia followed by skin wounding. Phenomena that are almost completely rescued by K14-TCL1 transgenic expression, in vivo. Since Tcl1 has a role in maintenance of a normal skin homeostasis in mice, involving both hair growth and epidermis, we used the approach of the expression chip analysis to unravel the pathways that are affected by loss of function and overexpression of Tcl1 in epidermal keratinocytes, by using Tcl1-/- and K14-TCL1;Tcl1-/- mice models. Our findings show that Tcl1 function involves the MAPK pathway, since Tcl1-/- shows increasing in p38MAPK phosphorylation linked to terminal differentiation/senescence/apoptosis of keratinocytes, while K14-driven overexpression shows increasing of p-Erk and p-Sapk/p-Jnk phosphorylations, linked to proliferation/commitment of keratinocytes. These signals flow through the MAPK cascade lead to altered AP1 factor function. In particular, the phosphorylation of AP-1 subunit c-Jun and c-fos transcriptional regulation and cellular localization result also affected.
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 4178. doi:1538-7445.AM2012-4178
Abstract 4182: Overexpression of Mig-6 suppresses endometrial cancer development and progression in ablation of Pten mice
Authors: Kim Tae Hoon , Kim Hong Im , Large Michael J. , Broaddus Russell R. , Lydon John P. , Jeong Jae-Wook 
Published: August 2012

Abstract
Endometrial cancer is the most common gynecological cancer. Estrogen-dependent endometrioid carcinoma is the most common type of endometrial cancer. In previous studies, we have identified mitogen-inducible gene 6 (Mig-6) as a downstream target of Progesterone Receptor (Pgr) action in the uterus. Ablation of Mig-6 in the murine uterus leads to the development of endometrial hyperplasia and estrogen-induced endometrial cancer. These results suggest that Mig-6 act as a tumor suppressor in endometrial cancer. To assess the effects of the overexpression Mig-6 and the PTEN/PI3K/AKT signaling pathways on uterine tumorigenesis, mice with Pten floxed (Ptenf/f) and LoxP-STOP-LoxP Mig-6 (R26Mig-6LSL) were bred to the PRCre mouse model to generate ablation of Pten and overexpression of Mig-6 in the uterus (PRcre+ R26Mig-6LSL Ptenf/f). PRcre+ R26Mig-6LSL Ptenf/f showed significantly increased survival time compared to PRcre/+ Ptenf/f mice. Double mutant mice showed significantly decreased uterine weight compared to PRcre/+Ptenf/f at 3 months of age. Gross morphology at 3 months of age showed that double mutant mice dramatically retarded the development of endometrial cancer compared to ablation of Pten alone. Histological analysis showed that endometrial adenocarcinoma with invasion into the myometrium was observed in the PRcre/+Ptenf/f mice at 3 months of age. However, double mutant mice did not develop endometrial cancer. Immunohistochemstry analysis showed significantly increased apoptosis and decreased proliferation at epithelial cells in PRcre+ R26Mig-6LSL Ptenf/f mice compared to PRcre/+ Ptenf/f mice at 3 months of age. The expression of pERK1/2 was significantly decreased in PRcre+ R26Mig-6LSL Ptenf/f mice compared to PRcre/+ Ptenf/f mice at 2 and 3 months of age. The expression of Pgr and its tartget genes was significantly increased in PRcre+ R26Mig-6LSL Ptenf/f mice compare to PRcre/+ Ptenf/f mice. However, the expression of Estrogen Receptor ≤ (Esr1) and its target genes was significantly decreased. The ability of Mig-6 to repress cancer development indicates that it exerts a tumor suppressor function in endometrial cancer. These results will contribute to the understanding of the molecular mechanism of tumorigenesis and to the development of therapeutic approaches for endometrial cancer.(Supported by NIH, R01 HD057873)
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 4182. doi:1538-7445.AM2012-4182
Abstract 4188: Whole transcriptome analyses of platinum-resistant ovarian cancer cells
Authors: Miller David F. , Lui Yunlong , Yan Pearlly , Rodriguez Benjamin , Lin Hai , Goel Shokhi , Jani Edra , Bhattrai Anurag , Koekesh Kevin , Guo Cong , Huang Tim H-M , Nephew Kenneth P. 
Published: August 2012

Abstract
Women with advanced stage ovarian cancer have a five-year survival rate of less than 25%. Although most patients respond to platinum-based chemotherapy, relapses are common, leading to platinum-resistant ovarian cancer, which is uniformly fatal. Similar to other malignancies, ovarian cancer progression is associated with transcriptional deregulation and such changes contribute to ovarian cancer progression and development of resistance to chemotherapy. In an effort to better understand the causes of acquired platinum resistance in ovarian cancer, we performed whole transcriptome analysis of platinum sensitive and resistant ovarian cancer cell lines. We used RNA-sequencing to identify candidate genes and pathways that contribute to platinum-resistant ovarian cancer. We detected altered mRNA expression of transcription factors (DMRT3, DMRT1, GATA1, EMX2, LHX1, SRY, SOX9, FOXL2, LHX9) and signaling pathway genes (RXFP2, AR, WT1, FGF9, RSPO1, TUSC3, NROB1, WNT4). Additionally, significant up regulation (&gt;20 fold increase) of the long non-coding RNAs (lncRNAs) HOTAIR and HOTTIP, which direct polycomb group and trithorax complexes to HOX promoters, was detected. We observed elevated HoxA gene expression (&gt; 100 fold in some cases) associated with increased HOTTIP lncRNA expression in the platinum resistant cells. Altered expression of genes associated with DNA methylation (DNMT1, DNMT3A, DNMT3B, DNMT3L MECP2, MBD3L1, MBD6, MBD2, MBD3L2, MBD5, MBD1, MBD3, MBD4) was also observed. Furthermore, the splicing patterns of BRCA1 and BRCA2 genes in platinum resistant cells were altered, resulting in splice variants lacking functional coding regions. Altered BRCA1 and BRCA2 splicing patterns were correlated with reduced expression levels for numerous splicing factors (A2BP1, PTBP1, RBM9, SFRS3, ARID3A, ARID3B, SF1). DNA methylation analysis indicated epigenetic derepression consistent with increased expression for gonad developmental genes (HOTAIR, HOTTIP, HOXA genes). Our data suggest that genes associated ovarian development and differentiation contribute to the development of platinum resistant ovarian cancer. We are currently conducting integrated data and bioinformatics analyses to further investigate changes found in platinum resistance.
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 4188. doi:1538-7445.AM2012-4188
Abstract 4191: HECT-type ubiquitin ligase ITCH targets lysosomal-associated protein multispanning transmembrane 5 (LAPTM5) and prevents LAPTM5-mediated cell death
Authors: Inoue Jun , Ishihara Takaya , Kozaki Ken-ichi , Imoto Issei , Inazawa Johji 
Published: August 2012

Abstract
Lysosomal-associated protein multispanning transmembrane 5 (LAPTM5) is a membrane protein on the intracellular vesicles. We have previously demonstrated that the accumulation of LAPTM5-positive vesicles was closely associated with the programmed cell death occurring during the spontaneous regression of neuroblastomas. While the accumulation of LAPTM5 protein might occur at the post-translational level, the molecular mechanism has been unclear. Here, we found that the level of LAPTM5 protein is negatively regulated by the degradation through ubiquitination by ITCH, an E3 ubiquitin ligase. ITCH directly binds to the PPxY motif of LAPTM5 via its WW domains and promotes ubiquitination through a HECT-type ligase domain. Overexpression of ITCH led to the degradation of LAPTM5 protein, and conversely, knockdown of ITCH by siRNA resulted in the stabilization of LAPTM5 protein. In addition, the inhibition of ITCH enhanced the cell death occurred by accumulation of LAPTM5 in neuroblastoma cells. These findings suggest that LAPTM5 is a novel substrate in terms of degradation by the ubiquitin ligase ITCH, and this system might act as a negative regulator in the spontaneous regression of neuroblastomas by preventing LAPTM5-mediated cell death.
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 4191. doi:1538-7445.AM2012-4191
Abstract 4207: CCN5/WISP-2 upregulates p27Kip1 in breast cancer cell lines through AKT/FOXO3a signaling
Authors: Haque Inamul , Banerjee Snigdha , De Archana , Jha Saheli Sinha , Banerjee Sushanta K. 
Published: August 2012

Abstract
CCN5 is a member of the CCN (cysteine rich 61-connective tissue growth factor-nephroblastoma-overexpressed) family of growth factors. Our studies have shown that CCN5 is mainly expressed in less aggressive human breast cancer cells (i.e., MCF-7 and ZR-75-1) and noninvasive lesion (i.e., atypical ductal hyperplasia and ductal carcinoma in situ), whereas its expression is minimally detected in moderately aggressive breast cancer cell lines (i.e., SKBR-3), and it is undetected in triple negative highly aggressive breast cancer cell line (i.e., MDA-MB-231) and invasive lesion. Ectopic expression of CCN5 has been shown to inhibit tumorigenicity in MDA-MB-231-xenograft models therefore suggesting that CCN5 is an anti-invasive molecule. The objective of the present study was to determine how CCN5 overexpression affects cell-cycle progression of breast cancer cells. We found knocking down of CCN5 in non-invasive breast cancer cells significantly downregulated the expression of p27Kip1, a tumor suppressor molecule. In contrast, enforced/ectopic expression of CCN5 overexpression in MDA-MB-231 breast cancer cells caused cell cycle arrest at G1 phase and dramatically reduced proliferation of these cells. CCN5 overexpression results in increased the stability as well as the expression of p27Kip1 protein. The regulation of p27Kip1 by CCN5 is mediated through AKT/FOXO3a signaling. Collectively, the studies suggest that CCN5 exerts its anti-invasive action through the regulation of p27Kip1.
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 4207. doi:1538-7445.AM2012-4207
Abstract 4216: Protein kinase C ≤ overexpression is associated with loss of membrane-associated E-cadherin and β-catenin in T47D xenograft breast tumors
Authors: White Bethany E. Perez , Zhao Huiping , Kundu Madhuchhanda , Molloy Mary Ellen , Tonetti Debra A. 
Published: August 2012

Abstract
Expression of protein kinase C ≤ (PKC∈) has been shown to be a clinically relevant indicator of tamoxifen response, recurrence and overall survival in breast cancer (Tonetti, 2003; Assender 2007). To study this association, we developed a model of PKC∈-overexpressing breast cancer by stable transfection of the prkca gene into T47D breast cancer cells (T47D/PKC∈, Tonetti, 2000). We have shown that PKC∈ induces a hormone-independent, tamoxifen-resistant phenotype in vitro and in vivo (Chisamore, 2001). This model is further characterized in vitro by increased migratory and invasive capability, expression of mesenchymal markers and reduced expression of adherens junctions and epithelial proteins (Perez White, AACR 2011). β-Catenin and E-cadherin are components of adherens junctions in normal epithelia and loss of E-cadherin is associated with worse outcome in breast cancer (Prat, 2010). Further, the reduction or cytoplasmic relocalization of β-catenin has been associated with poor prognosis (Lopez-Knowles, 2010; Dolled-Filhart, 2006) though the processes upstream or downstream of these changes are not well characterized in breast cancer. Therefore we hypothesized that xenograft tumors derived from T47D/PKC∈ cells would have loss of membrane-associated β-catenin and E-cadherin. Immunofluorescence staining showed cytoplasmic localization of β-catenin and E-cadherin in T47D/PKC∈ tumors in sharp contrast to membrane association in T47D/neo (vector control) tumors. Western blot showed reduction in the level of E-cadherin in T47D/PKC∈ tumor samples but no change in the level of β-catenin compared to T47D/neo tumors. Based on this, we next wanted evaluate the β-catenin degradation pathway mediated by glycogen synthase kinase-3β (GSK-3β). Cellular extracts show an increase in the levels of the serine 9 inhibitory phosphorylation of GSK-3β in T47D/PKC∈ cells but no increase in total protein compared to T47D/neo cells. Treatment with the proteasomal inhibitor MG132 (10 μM) for 2 h did not increase the levels of β-catenin in vitro in T47D/PKC∈ cells. Current data indicate a correlation between PKC∈ expression and loss of membrane-associated β-catenin and E-cadherin. Further, β-catenin is stabilized in the cytoplasm of T47D/PKC∈ cells possibly allowing for nuclear localization and downstream gene transcription. Taken together with previous data, PKC∈ correlates with markers of poor outcome in addition to hormone-independence and tamoxifen-resistance suggesting that PKC∈ may play a central role in breast cancer progression.
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 4216. doi:1538-7445.AM2012-4216
Abstract 4226: CD44 increases drug resistance by protecting FBXO21 mediated ubiquitination of P-glycoprotein
Authors: Ravindranath Abhilash K. , Kaur Swayamjot , Rodriguez Lorna 
Published: August 2012

Abstract
Drug resistance and metastases are major causes of treatment failure in cancer. These two important but not clearly related aspects in the biology of cancer have been extensively studied, but not until recently has there been evidence that these phenotypes are functionally linked. Two proteins, P-glycoprotein (P-gp) and CD44 are well known determinants of multidrug resistance and metastases, respectively. P-gp, the product of the ABCBC1 gene is a transmembrane ATP-dependent transporter that confers drug resistance to cancer cells. CD44 is a membrane protein implicated in metastases and has been identified as a “stem cell” marker for various types of cancer. Previously, we reported about a physical and functional interaction between P-gp and CD44. We found that the two proteins co-immunoprecipitate and co-localize within the cell membrane. When we introduced CD44 into CD44 (-) breast cancer cell lines, we found that P-gp expression was also induced both at the mRNA and protein level and the cells became drug resistant. In the present work we created a yeast-2-hybrid system that corroborates the physical interaction between the two proteins. We generated point mutants of the CD44 intracytoplasmic domain at two different serine residues known to be phosphorylation sites and show that when Ser 291 of CD44 is mutated, P-gp function is completely inhibited and the cells revert to drug sensitive in face of P-gp expression. We therefore hypothesized that CD44 could be stabilizing P-gp. We first determined that P-gp is ubiquitinated and degraded by the proteasomal pathway. We then screened a siRNA E3 ligase library and found several candidates for P-gp E-3 ligases. We tested FBXO21, which is in the FBOX family of ligases and does not have a known function yet. We demonstrated that FBXO21 ligase binds, ubiquitinates, and degrades P-gp. Furthermore, we show that CD44 inhibits FBXO21 directed ubiquitination of P-gp. Our findings are key to the understanding of P-gp induced drug resistance and reveal a new control mechanism of P-gp expression. Our work uncovers CD44 phosphorylation at Ser 291 as an excellent and very specific new drug target that would distinctively affect drug resistant cancer cells that are CD44 positive, such as cancer stem cells.
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 4226. doi:1538-7445.AM2012-4226
Abstract 4227: Sensitizing resistant ovarian cancer to chemotherapy through inhibition of small GTPases
Authors: Goncharov Kirill , Zeineldin Reema R. 
Published: August 2012

Abstract
Platinum- or paclitaxel-resistance is a major problem in women with advanced ovarian cancer (OVCA) and that confers a poor prognosis for patients. Consequently there is a great need to identify new drugs and drug targets for the management of residual and recurrent metastatic OVCA. About 90% of OVCA starts on the ovarian surface epithelium, but individual cells or multicellular aggregates (MCAs) shed into the peritoneal cavity and contribute to OVCA's metastasis into adjacent organs. These MCAs are resistant to apoptosis and to radio- and chemo-therapy. In OVCA, resistance to chemotherapy and apoptosis has been linked to the small GTPases, Rac1 and Cdc42, and their downstream effectors. Identifying compounds that disperse MCAs through disrupting adhesions would sensitize this resistant subpopulation to chemotherapy. We hypothesize that inhibition of one or both of these GTPases disrupts MCAs and sensitizes drug-resistant OVCA cells to respond to chemotherapeutic agents. We assessed if chemical inhibition of Rac1 or Cdc42 would sensitize drug-resistant OVCA monolayers and in vitro MCAs to cisplatin's cytotoxicity. The OVCA cell lines evaluated were OVCA 429 and SKOV-3ip. The inhibitors we used included: (1) NSC 23766, a Rac1-specific inhibitor, (2) ML141, a Cdc42-specific inhibitor, (3) Toxin B, an inhibitor of Rac, Cdc42 and Rho, and (4) R-naproxen, an inhibitor of Rac1 and Cdc42 (based on our data). We found that Rac1 and Cdc42 inhibitors disperse MCAs in a liquid overlay assay. Furthermore, these inhibitors sensitized OVCA cells to cisplatin's cytotoxic effect. Finding drugs that increase efficacy of chemotherapeutic agents against resistant OVCA cell populations is of particular importance. Thus far, GTPases have not been extensively examined as therapeutic targets, but they offer new opportunities for OVCA therapy. Our findings indicate that Rac1 and Cdc42 inhibitors disperse MCAs and improve their response to chemotherapeutic agents. This could increase the effectiveness of intraperitoneal chemotherapy and improve patient outcomes and survival. Since one of these inhibitors is R-Naproxen (an FDA approved off-patent drug), it has potential for rapid clinical application.
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 4227. doi:1538-7445.AM2012-4227
Abstract 4232: GFP imaging of DNA repair after UV irradiation of cancer cells
Authors: Tome Yasunori , Yano Shuya , Maehara Hiroki , Efimova Elena V. , Kanaya Fuminori , Tsuchiya Hiroyuki , Tomita Katsuro , Bouvet Michael , Hoffman Robert M. 
Published: August 2012

Abstract
The ability to image DNA repair in cancer cells after irradiation as well as its inhibition by potential therapeutic agents is important for the further development of radiotherapy of cancer. The relocalization of GFP fused to the chromatin-binding domain of a check-point-adapter protein 53BP1 was imaged after UV irradiation of breast cancer and MiaPaca-2 human pancreatic cancer cells. 53BP1 is a DNA repair protein that is over-expressed when double-stranded breaks occur in DNA. During live-cell imaging, 53BP1-GFP foci formation was observed within 15 minutes after UV irradiation. Most 53BP1 foci resolved by 90 min. To block UV-induced double stranded break (DSB) repair in cancer cells, we targeted poly (ADP-ribose) polymerase (PARP) with ABT-888 (veliparib). PAPR inhibition markedly enhanced UV-irradiation-induced foci persistence, even more than 90 min after UV irradiation, and decreased cell proliferation of breast and pancreatic cancer cells. The results suggest UV-irradiation and PAPR inhibition are a promising therapeutic combination for breast and pancreatic cancer.
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 4232. doi:1538-7445.AM2012-4232