bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2701: RORα suppresses breast tumor progression by inducing cell polarization and inhibiting cell invasion
Authors: Xiong GaoFeng , Xu Ren 
Published: August 2012

Abstract
Background: Disruption of tissue polarity is one of hallmarks of breast cancer development, which is associated with cell invasion and cancer dissemination. Therefore, identifying proteins and pathways that modulate cell polarity is crucial not only to advancing our knowledge of breast cancer, but also to discovering potential therapeutic targets. Methods: To identify potential regulators of tissue polarity, we analyzed over-represented DNA motifs in the promoter regions of the polarization genes that are significantly up-regulated genes in polarized human mammary epithelial cells in a physiologically relevant three-dimensional (3D) culture system. We assessed the protein levels of RORα by immunoblotting and immunohistochemistry in malignant and non-malignant human mammary epithelial cells as well as human breast cancer tissue array. To explore the functional significance of RORα down-regulation the malignance of breast cancer cells, we restored RORα expression in malignant T4-2 cells, MDA231 cells and silenced RORα expression in non-malignant S1 cells. The growth and malignant phenotypes of these cells were examined in 3D culture and xenograft model. Results: Results from promoter analysis suggest that RORα is a potential regulator of mammary tissue polarity and is inactivated in disorganized HMECs. Expression of RORα protein is significantly reduced in malignant breast cancer cell lines and this reduction is associated with disruption of acinar structure in 3D culture. Both mRNA and protein level of RORα were significantly reduced in human breast cancer tissues. Restoring RORα expression in T4-2 and MDA-MB 231 cells significantly suppressed proliferation, invasion and the malignant phenotypes in 3D culture. Silencing RORα expression in non-malignant S1 cells disrupts the polarized acinar morphogenesis. Restoring RORα expression in T4-2 and MDA-MB 231 cells also inhibits the tumor growth in nude mice. Moreover, patients with reduced expression of RORα in cancer tissue have significantly shorter survival. Conclusion: Together these results indicate that inactivation of RORα promotes the breast cancer development and progression by enhancing cell invasion and disturbing normal tissue architecture. RORα provide a potential therapeutic target for breast 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 2701. doi:1538-7445.AM2012-2701
Abstract 2702: Effects of Src and IGF1R inhibition on acquired endocrine therapy resistant breast cancer
Authors: Liu Shuyling , Meng Xiaolong , Liu Wenbin , Miller Todd , Lu Yiling , Zhang Fan , Arteaga Carlos L. , Mills Gordon B. , Gonzalez-Angulo Ana M. 
Published: August 2012

Abstract
Effective standard therapy for hormone receptor-positive (HR+) breast cancer targets the estrogen receptor (ER). However, a significant proportion of women with HR+ breast cancer relapse. Furthermore, the majority of women with metastatic HR+ breast cancer develop resistance to endocrine therapy. Adaptive cross-talk between ER and growth factor receptor pathways including IGF1R and Src is involved in acquired endocrine therapy resistance. To determine effects of adding dasatinib (D), Src inhibitor, and/or anti-IGF1R Ab MK0646 (M) to the ER antagonist fulvestrant (F) in an acquired endocrine therapy resistant breast cancer, we used long-term estrogen-deprived (LTED) derivative of ER+ breast cancer cell lines, MCF-7/LTED and HCC-1428/LTED. Parental and LTED cells were treated with variable combinations of F, D and M, followed by determinations of drug effects on cell growth, migration, and invasion in vitro and tumor growth in vivo. We demonstrated that LTED cells were resistant to F alone, comparing parental cells (P&lt;0.05) in cell growth, migration and invasion. Addition of D to F appeared to be synergistic in all systems including cell growth, cell migration and invasion. However, the addition of M to F or to F+D appeared inhibition on cell growth in monolayer with low-serum medium, but not to significantly add inhibitory effects on cell growth in 3D and cell migration and invasion. The effects of IGF-1R antibody, MK0646, on cells growth in monolayer showed not consistent with 3D, which might be due to growth factors in the matrigel, although we used growth factors decreased matrigel. To verify the effects of the drugs on tumor growth in vivo, we developed xenograft models using MCF-7/LTED cells and treated the mice with F, D, and M along or variable combinations. The study demonstrated that all the combinations of F+D+M, F+D, and F+M (from P&lt; 0.05 to &lt;0.001 in viable time points) show inhibited the tumor growth comparing vehicle or F alone. The inhibitory effect of F+D+M is higher than F+D and F+M. In summary, the addition of dasatinib to fulvestrant appeared to be synergistic in all systems including cell growth, cell migration and invasion and tumor growth in vivo. The addition of MK0646 to fulvestrant mildly inhibited MCF-7/LTED cell growth and xenografts growth, but not cell migration and cell invasion.
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 2702. doi:1538-7445.AM2012-2702
Abstract 2703: Final results of a phase 2 trial using a novel, non-anthracycline neoadjuvant chemotherapy regimen in Her2-positive breast cancer
Authors: O'Regan Ruth M. , Gabram Sheryl , Styblo Toncred , Rizzo Monica , Wood William , Srinivasiah Jayanthi , Jonas William , Schnell Fred , Adams Amy , Nahta Rita , Zelnak Amelia 
Published: August 2012

Abstract
Background: The addition of trastuzumab to preoperative chemotherapy for Her2-positive breast cancers has been shown to increase pCR rate, which correlates with improved outcome. The purpose of this study was to evaluate the efficacy of trastuzumab in combination with dose-dense nab-paclitaxel followed by weekly vinorelbine. Methods: Patients with Stage I (&gt;1.0 cm), II, or IIIA Her2-positive (defined as either immunohistochemical 3+ of fluorescence in situ hybridization-positive) breast cancer received nab-paclitaxel 260 mg/m2 iv every 2 weeks for 4 cycles in combination followed by vinorelbine 25 mg/m2 iv weekly with simultaneous trastuzumab (4 mg/kg loading dose then 2 mg/kg weekly) for 20 weeks. Tissue was collected at baseline, at optional midway biopsy, and post-therapy. Primary endpoint was pCR rate; secondary endpoints included response rate and toxicity. Cardiac evaluation was performed at baseline, after 4 cycles of nab-paclitaxel, after 12 weeks of vinorelbine and every 3 months thereafter per standard practice guidelines. Results: To date, 27 patients have been accrued (3/2008 to 6/2011). 24 patients are currently evaluable for primary endpoint. Patients were accrued from a university center (48.2%), county hospital (11.1%), and community sites (40.7%). Median age was 49.5 years (34-64). Median tumor size was 4.0 cm (1.5-7cm). 14 of 27 patients (51.9%) were clinically node-positive at study entry. 11 patients were African American (40.7%), 16 were Caucasian (59.3%). The regimen was well-tolerated: 3 patients experienced grade 3 neuropathy; 6 patients had grade 3 neutropenia; 1 patient had trastuzumab held for asymptomatic decrease in left ventricular ejection fraction. 18 of 24 patients (75%) had complete clinical response rate. 6 of 24 patients (25%) had partial clinical response. 11 of 24 patients (45.8%) had pCR. Conclusions: The combination of preoperative trastuzumab with dose-dense nab-paclitaxel followed by vinorelbine was well-tolerated and resulted in a high rate of pCR in Her2-positive, early-stage breast cancer. Final results and correlative studies will be reported.
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 2703. doi:1538-7445.AM2012-2703
Abstract 2704: Tetraspanin CD151 drives mammary tumor onset and metastasis by coordinating integrin-dependent cell adhesion, motility, survival and signaling
Authors: Deng Xinyu , Hoff John , Novak Marian , Kaetzel David , Hemler Martin E. , Yang Xiuwei H. 
Published: August 2012

Abstract
The ErbB2+ subtype of human breast tumors remains a significant threat to women's health, as they are highly prone to recurrence or metastasis, and development of drug resistance. Here we report that CD151, a member of the tetraspanin family and a close partner of the laminin-binding (LB) integrins (≥3α1 and α6β4), contributes to the onset and malignancy of ErbB2-induced mammary tumors. By crossing gene-targeted mice onto a clinically-relevant MMTV-ErbB2 transgenic model, we demonstrated that deletion of CD151 significantly impaired the onset and metastasis of mammary tumors in mice. Our subsequent analyses of cell lines derived from mouse primary tumors showed that loss of CD151 decreased integrin-mediated cell-ECM adhesion and cell-cell contacts. Also, for ErbB2-overexpressing MCF-10A cells cultured in 2D or 3D, ablation of CD151 markedly reduced tumor cell motility, invasion and survival. However, only MAPK and FAK kinases among an array of signaling molecules downstream of integrins and ErbB receptors, exhibited a decreased activation in response to CD151 disruption. Importantly, there were corresponding changes in the activation and signaling of α6β4 integrin, as reflected by decreased phosphorylation of multiple serine residues at its cytoplasmic domain. Also, the cross-talk between integrins and ErbB receptors was strongly inhibited. Meanwhile, our analyses of clinical dataset revealed a strong correlation between CD151 gene expression and patients’ metastasis-free survival. Taken together, our results demonstrate that tetraspanin CD151 drives ErbB2-induced mammary tumorigenesis by coordinating the function and signaling of LB integrins. This newly-identified crucial role of CD151 offers a strong therapeutic potential for the treatment of breast cancer patients.
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 2704. doi:1538-7445.AM2012-2704
Abstract 279: Small interfering RNA targeting CD44 blocks EGFR signaling in head and neck squamous cell carcinoma (HNSCC)
Authors: Perez Aymee , Jacobs Mark , Wen Judy , Pereira Lutecia , Neskey David M. , Franzmann Elizabeth J. 
Published: August 2012

Abstract
INTRODUCTION: Head and Neck Squamous Cell Carcinoma (HNSCC) is a disease that accounts for 90% of the 600,000 new diagnoses of head and neck cancers worldwide each year. CD44 is a purported cancer stem cell (CSC) marker, and its colocalization with EGFR has been proposed to activate tyrosine kinase (TK) and mitogen-activated protein kinase (MAPK). Therapies tend to have dismal cure rates. Understanding the interaction between CD44 and EGFR may result in improved therapies for HNSCC. METHODS: To evaluate the effect of CD44 on EGFR, we inhibited CD44 expression in a CD44-overexpressing HNSCC cell line, CAL27, using the siRNA method. The cell line was stably transfected with a DNA plasmid designed to knock down the expression of CD44. We then performed western blots examining CD44 and phosphorylated EGFR (Y1068) in siRNA knockdown clones and in scrambled sequence, followed by implantation of the CD44siRNA clones and scramble controls in nude mice. The mice were sacrificed, and the tumors were embedded in paraffin for IHC analysis. CD44 and EGFR colocalization was examined in 5 HNSCC cases and in CAL 27 xenografts by immunohistochemistry (IHC) and laser scanning confocal microscopy (LSCM). RESULTS: Downregulation of CD44 by siRNA in CAL 27 cells inhibited constitutive EGFR phosphorylation in vitro and in vivo. Knocking down of CD44 by siRNA reduced the tumor growth in mice compared to CAL 27 and scrambled siRNA. CD44 and EGFR coexpression and colocalization were observed in 80% (4/5) of HNSCC cases and in CAL 27 xenografts. CONCLUSION: Based on these studies, targeting CD44 may provide an additional therapeutic option for HNSCC that does not respond favorably to other treatments. Anti- CD44 therapy in HNSCC may target the cancer stem cell population and alter EGFR signaling.
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 279. doi:1538-7445.AM2012-279
Abstract 2814: Potent and selective small molecule inhibitors of polo-like kinase 1: Biological characterization
Authors: Frame Sheelagh , Aspinall Claire , O'Neil Robert , Hollick Jonathan , Taylor Stephen , Hupp Ted , Blake David , Zheleva Daniella I. 
Published: August 2012

Abstract
Polo-like kinase 1 (Plk1) is one of the emerging new generation of anti-mitotic targets. Plks are a family of serine-threonine kinases involved in the regulation of mitosis and maintenance of DNA integrity. Plk1 is required for almost every step of mitosis: promotes mitotic entry, contributes to centrosome maturation, regulates kinetochore assembly, contributes to spindle assemble checkpoint and initiates mitotic exit. Besides promoting proliferation, Plk1 overexpression contributes to oncogenesis by promoting chromosome instability and aneuploidy. Overexpression of Plk1 is associated with tumor development and many cancers have elevated Plk1 levels compared to surrounding normal tissues. Numerous studies have shown that Plk1 expression levels correlate with disease progression, invasiveness and poor patient prognosis. Furthermore, pre-clinical studies have demonstrated that cancer cell proliferation is blocked in vitro and in vivo via inhibition of Plk1 using siRNA or small molecule inhibitors. Collectively, these observations support the selection of Plk1 as an attractive target for cell cycle-directed cancer therapy and several small molecule inhibitors are currently being investigated in clinical trials. Using a de novo ligand design approach we have identified pyrimidodiazepinone small molecules, which are ATP-competitive, highly selective and potent Plk1 inhibitors. These molecules have good drug-like properties, oral bioavailability and efficacy in mouse xenograft models. To characterize the cell sensitivity toward the Plk1 inhibitors we have used washout and outgrowth assays in a panel of oesophageal, lung and colon cancer cell lines. The anti-proliferative activity of Plk1 inhibitors was correlated with the Plk1 expression level, p53 and Ras mutational status. Generally, we found that cell lines harbouring p53 mutations are more sensitive towards these inhibitors. Time-lapse microscopy and flow cytometry studies of RKO cell line (WT p53) treated with Plk1 inhibitors demonstrated that a proportion of cells arrested just before the G2-/-M transition and were able to resume normal proliferation upon compound removal. These results suggest that Plk1 inhibitors should have better therapeutic window when used for treatment of tumors with mutant p53, p53 mutational status could be used as a patient stratification marker, and tumor types with high frequency of p53 mutations, such as oesophageal cancer, could be suitable therapeutic indications for Plk1 inhibitors.
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 2814. doi:1538-7445.AM2012-2814
Abstract 2817: Preclinical studies of the PI3K/mTOR dual inhibitors in endometrial cancer cell lines
Authors: Yuan Jing , Garza Scott J. , Cao Joan , Fisher Timothy S. , Lee Nathan V. , Eisele Koleen , Pasis Angela , Hook Kenneth , Christensen James G. , Kan Julie L. 
Published: August 2012

Abstract
The PI3K pathway plays a pivotal role in many cellular functions that include regulation of cell proliferation, survival, growth, angiogenesis, and motility. Dysregulation of the PI3K/AKT pathway is a common occurrence in cancer and could be a result of mutations in PIK3CA and PTEN, as well as loss of heterozygosity of PTEN. In endometrial cancer patients, the most frequent aberration is the activation of the PI3K/mAKT pathway with; (1) 80% loss of PTEN function and 30% PIK3CA mutations in type I endometrial cancer and (2) 20% PIK3CA mutation and 46% PIK3CA amplification in type II endometrial cancer. In this study, we investigated the functional consequences of the dual PI3K/mTOR inhibitors PF-04691502 and PF-05212384 in endometrial cancer cell lines for antiproliferative effects, pathway signaling inhibition and tumor growth inhibition. Both compounds had antiproliferative activity in vitro that translated to tumor growth inhibition in vivo. Moreover, in the MFE-280 xenograft model that harbors a PIK3CA mutation (P1047R), the dual PI3K/mTOR inhibitors showed tumor regression. These studies support the use of the dual PI3K/mTOR inhibitors for endometrial 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 2817. doi:1538-7445.AM2012-2817
Abstract 2818: Aurora B kinase inhibitor barasertib (AZD1152) and cytarabine in combination exert more than additive cytotoxicities against cytarabine-resistant acute myeloid leukemia cells in vitro
Authors: Yamauchi Takahiro , Ueda Takanori 
Published: August 2012

Abstract
The majority of patients with acute myeloid leukemia (AML) initially achieve complete remission by cytarabine (ara-C)-based chemotherapy, but many relapse with resistant disease. Aurora B kinase is involved in the spindle assembly checkpoint component of the mitotic process. Barasertib (formerly AZD1152), a selective inhibitor of aurora B kinase, provided an overall hematological response rate of 25% in AML patients in a phase I/II study, which warrants further investigation. To see the feasibility of the incorporation of this new agent to the standard induction chemotherapy, we evaluated the combination effect of barasertib with ara-C against leukemic cells in vitro. Cultured human leukemia HL-60 cells and ara-C-resistant variant HL-60/ara-C cells were used. Growth inhibition effects were evaluated by using the XTT assay. The cell cycle distribution and the induction of apoptosis were determined by flowcytometric analysis. Autophosphorylation of aurora B was assessed by Western blotting. The XTT assay determined that the 50%-growth inhibitory concentrations of ara-C were 100 - 300 nM for HL-60 cells and 4,000 - 5,000 nM for HL-60/ara-C cells, respectively. When HL-60 cells were treated with barasertib-hQPA, the active compound of barasertib, the cells exhibited an increase in the percentage of &gt; 4N at 48 h with the subsequent induction of sub-G1 population. Autophosphorylation of aurora B was inhibited by barasertib-hQPA simultaneously. When the cells were treated with ara-C, the accumulation at G2-M phase and the subsequent increase in sub-G1 phase were observed. When the cells were treated with barasertib-hQPA and ara-C in combination, the treatment induced the greater-than-additive induction of sub-G1 population. However, the augmentation was brought about only when the cells were treated with barasertib prior to ara-C or both simultaneously. Barasertib-hQPA similarly altered the cell cycle, inhibited autophosphorylation of auroa B, and induced apoptosis in HL-60/ara-C cells. Low concentrations of ara-C failed to modify cell cycle distribution without the induction of apoptosis in HL-60/ara-C cells. Nevertheless, the sequential combination between barasertib-hQPA and a moderate concentration of ara-C augmented the sub-G1 population. In conclusion, the combination of barasertib with ara-C provided greater cytotoxicity than barasertib alone in both ara-C-sensitive and ara-C-resistant AML cell lines in vitro. The sequential administration of barasertib with ara-C may be promising against ara-C-refractory AML.
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 2818. doi:1538-7445.AM2012-2818
Abstract 2821: The PKC-iota inhibitor ICA-1 overcomes chemoresistance and induces cell death in glioblastoma multiforme
Authors: McCray Andrea N. , Acevedo-Duncan Mildred 
Published: August 2012

Abstract
Glioblastoma multiforme is a very aggressive brain cancer that is refractory to most chemotherapeutics. The standard of care for glioblastoma patients is the administration of temozolomide following surgery. However, temozolomide provides an approximately 20% enhanced survival rate. Therefore, it is imperative to develop other novel chemotherapeutics to better enhance the survival rate and induce tumor regression in patients. A potential candidate for a pre-clinical glioblastoma study is the novel chemotherapeutic, ICA-1. ICA-1 is a PKC-iota inhibitor which specifically inhibits PKC-iota and not its homologue, PKC-zeta. Results demonstrated that ICA-1 inhibited cell proliferation rates in a range of T98G glioblastoma concentrations in vitro. Also, results showed that low density T98G cultures which have a high proliferation status and high S-phase promotion concomitantly demonstrated resistance to ICA-1 treatment. However, high density T98G cultures which have a lower proliferation status and low S-phase promotion are concurrently chemosensitive toward ICA-1. At 48h post ICA-1 treatment, the majority of cells in the high density cultures were in G0/G1 with a rise of cells in this phase of the cell cycle shown by day 5 post-treatment. Conversely, between 48h and day 5, 30-44% of cells from the low density cultures were in S phase irrespective of ICA-1 therapy. Furthermore, by day 5 post-treatment, ICA-1 induced significant cell death in T98G cells only at higher ranges (i.e., 20-40 microM of ICA-1). Interestingly, 40 microM ICA-1 caused a significant cell death rate of 45% when 7,500 cells were seeded into a 24-well plate on Day 0 followed by ICA-1 exposure on the next day. Forty microM ICA-1 induced 15% cell death when 3,750 cells were seeded. There was a stepwise increase in the amount of ICA-1 required to induce cell death as the cell concentration increased (i.e., high density T98G cultures required elevated levels of ICA-1). Therefore, the data suggested that the G0/G1 phase glioblastoma cells (i.e., the higher cell concentrations) were more sensitive to 40 microM ICA-1 therapy. Whereas, the S phase glioblastoma cells were less sensitive to the ICA-1 therapy. Future animal models may show that the more aggressive the tumor becomes, the greater the potential for the effectiveness of ICA-1 (i.e., greater chemosensitivity).
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 2821. doi:1538-7445.AM2012-2821