bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1966: Role of Wnt-Beta-Catenin signals in the control of vascular mimicry in TNBC
Authors: Leyland-Jones Brian , Carlson Jennifer H. , De Pradip , Dey Nandini 
Published: August 2015

Abstract
Background: TNBC or basal-like subtype of breast cancer confers poor clinical outcome mostly due to its inherent aggressive nature and its high frequency of metastasis. Malignancy in TNBC is associatedwith micro-vascular proliferations. Vascular Mimicry (VM) of solid tumor is an endothelium-independent matrix-embedded, blood-perfused non-angiogenic micro-circulatory phenomenon. VM of tumor cells refer to the characteristic plasticity of aggressive cancer cells forming de novo vascular networks which perfuse rapidly growing tumors, transporting fluid from leaky vessels and/or connect with the constitutional endothelial-lined vasculature. In a study comparing the VM in three subsets of BC, the presence of VM was more profoundly observed in TNBC than in luminal and HER2+ subtypes.
Hypothesis: Recently we have identified a differential activation of Wnt-b-Catenin pathway (WP) in TNBC (Dey et al., PLOSONE; 2014) and demonstrated that Wnt signaling in TNBC is association with metastasis (Dey et al., BMC Cancer 2013). Since TNBC is an aggressive form of BC and VM is associated with the aggressiveness / poor outcome in many solid tumors including BC, we hypothesized that the upregulation of WP in TNBC may have a functional relationship with VM.
Methods: Four strategies were used to study the role of WP in VM. They are (1) Wnt-receptor interaction by using WntC59, (2) Wnt cytosolic signaling by using XAV939, (3) Wnt nuclear signaling by using sulindac sulfide and beta-catenin SiRNA and (4) Wnt-regulating pathway by using pan-PI3K inhibitor (LY294002 and SF1126). The signaling of VM was characterized by bevacizumab (HUVEC cell cord formation used as positive control).
Results: Using pharmacological and genetic tools, we demonstrated that perturbation of WP (1) at its different nodes and (2) via its upstream regulatory pathway (PI3K) can regulate VM in TNBC cells. Data showed that (1) sulindac sulfide, (2) XAV939 and WntC59 and (3) LY294002 or SF1126 (which decreased pGSK3beta) caused an abrogation of VM in TNBC cell lines while bevacizumab failed to affect the vessel formation. Considering the involvement of VM in mediating the aggressive/metastatic nature of TNBC, we finally tested the effect of downregulation of WP on VM in brain metastasis specific EGFP-tagged MDA-MB231BR cells using a real time recording device (Incucyte) to demonstrate that VM in these cells is regulated by WP.
Significance: To our knowledge, this is the first report to demonstrate a direct functional role of WP in the regulation of VM in TNBC.
Citation Format: Brian Leyland-Jones, Jennifer H. Carlson, Pradip De, Nandini Dey. Role of Wnt-Beta-Catenin signals in the control of vascular mimicry in TNBC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1966. doi:10.1158/1538-7445.AM2015-1966
Abstract 1968: Activation of AKT negatively regulates the pro-apoptotic function of death-associated protein kinase 3 (DAPK3) in prostate cancer
Authors: Das Trinath P. , Papu John Arokya MS , Roy Ram V. , Rao Sandhya R. , Alatassi Houda , Damodaran Chendil , Ankhem Murali M. 
Published: August 2015

Abstract
Activation of AKT plays a central role by inducing pro-survival signaling pathways, promotes cell growth and inhibits apoptosis in human malignancies including prostate cancer. Higher expression of pAKT is correlated with aggressiveness of the prostate cancer. Published evidences suggest that inhibition of survival kinases may utilize the current therapeutic modalities to sensitize the prostate cancer cells more significantly. Indeed, numbers of small molecules or peptides are being developed to inhibit either AKT or its upstream kinase PI3K to inhibit the growth of human malignances. Death-associated protein kinase 3 (DAPK3), a serine/threonine kinase governs many signaling pathways including induction of apoptosis.
This lead the way to focus our research on small molecules which can inhibit AKT activation and induce DAPK mediated apoptosis in CaP cell lines. To begin with, we identified a small molecule which binds to AKT kinase domain with a predicted affinity of ∼11.0 Kcal/mol. The amino acid residues of AKT-1 within 4 Å of the best docking site of this small molecule, 6-dimethyl, dihydro pyranone (6ddp), includes ARG-4, SER-7, LEU-156, GLY-157, LYS-158, GLY-159, PHE-161, VAL-164, LYS -179, GLU-191, HIS-194, GLU-234, ASP-274, MET-281, ASP-292, GLY-294,LEU-295, and PHE-438. The hydroxyl group of 6ddp likely forms a hydrogen bond with the nitrogen on the side chain of HIS-194. 6ddp inhibited pAKT (ser473) expression which concomitantly induced DAPK1 expression resulting in the growth inhibition of CaP cell lines. Similar results were obtained when a pharmacological inhibitor of AKT was used which resulted in DAPK induced apoptosis of CaP cells. Subsequently, we examined the DAPK3 activation in prostate cancer samples, which significantly showed a higher expression in normal prostate samples. On the contrary, reduced expression with low level was observed with the progression of disease. Currently, our study focuses on the kinase and phosphatase interaction network by mass spectrometric analysis of protein complexes. Understanding the mechanism of DAPK3 mediated AKT inhibition, may strengthen the therapeutic window for prostate cancer without causing much or any toxicity
Citation Format: Trinath P. Das, Arokya MS Papu John, Ram V. Roy, Sandhya R. Rao, Houda Alatassi, Chendil Damodaran, Murali M. Ankhem. Activation of AKT negatively regulates the pro-apoptotic function of death-associated protein kinase 3 (DAPK3) in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1968. doi:10.1158/1538-7445.AM2015-1968
Abstract 1979: Regulation of the oncogene ZNF217 by localization in breast cancer
Authors: Messana Matthew J. , Littlepage Laurie E. 
Published: August 2015

Abstract
Poor prognosis in breast cancer patients occurs when malignant tumors adapt to environmental insults, become resistant to chemotherapy, evade immune surveillance and metastasize to other tissues. Tumors are thought to arise from individual cells with multiple mutations, including amplification of genomic regions that provide a growth advantage. A region on human chromosome 20 called 20q13 is increased in ∼25% of early stage human breast cancers and correlates with poor prognosis in patients. We have studied a novel oncogene ZNF217 within this region. ZNF217 is key in promoting breast cancer: it is not only a prognostic indicator of breast cancer progression in patients who have the worst prognosis but also is itself a drug target and/or marker of patient response to therapy. We find that ZNF217 protein is expressed most strongly in a small subset of cells within normal mammary epithelium and localizes predominantly in the nucleus of mammary epithelial cells. In contrast, the localization of ZNF217 is heterogeneous in breast tumors, with localization in both the nucleus and cytoplasm. Moreover, a truncated form of the protein localizes exclusively in the cytoplasm. We hypothesize that ZNF217 cytoplasmic localization affects ZNF217 function during cancer progression and can be used to predict poor prognosis in breast cancer patients. We have stained human breast tissue and human mammary epithelial cells for ZNF217 and find heterogeneous localization of ZNF217 across the samples. We now will identify the regions of ZNF217 that are required for ZNF217 localization in the nucleus and cytoplasm. We will utilize integrated biological approaches to determine the consequences of mis-localization of ZNF217 on cancer progression. Using our truncation mutants, we will determine which regions of ZNF217 are required for oncogenesis by overexpressing ZNF217 truncations in mammary epithelial cells and using these cells in a variety of assays that model steps in cancer progression assays that have previously shown that ZNF217 promotes cancer progression.
Citation Format: Matthew J. Messana, Laurie E. Littlepage. Regulation of the oncogene ZNF217 by localization in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1979. doi:10.1158/1538-7445.AM2015-1979
Abstract 1983: Aryl hydrocarbon receptor activates NDRG1 transcription under hypoxia in breast cancer cells
Authors: Li En-Yu , Huang Wei-Yung , Tsai Mong-Hsun , Chuang Eric Y. , Lai Liang-Chuan 
Published: August 2015

Abstract
Hypoxia has been intensively investigated over past decades based on the observations that hypoxic tumors were more resistant to therapy and had a worse prognosis. Previously, we reported that N-myc downstream-regulated gene 1 (NDRG1) was strongly up-regulated under hypoxia and may play an important role in tumor adaptation to fluctuation of oxygen concentrations. However, the regulatory mechanism of NDRG1 under hypoxia remains elusive. Therefore, the purpose of this study is to identify the novel transcription factors that regulate NDRG1 and to investigate the functional roles of NDRG1 in hypoxia. In silico analysis predicted binding sites of aryl hydrocarbon receptor (AHR) existing in the NDRG1 promoter. Western blotting showed that nuclear AHR was up-regulated in the presence of cobalt and hypoxia. Immunofluorescence staining and chromatin immunoprecipitation assays showed that AHR translocated to nuclei and bound to NDRG1 promoter in hypoxia. Luciferase reporter assays further showed that the binding site of AHR at -412 ∼ -388 bp played a crucial role in regulating NDRG1 under hypoxia-mimicking conditions. Moreover, hypoxia-mimetic induction of NDRG1 by was attenuated by knockdown of AHR expression using short interfering RNA. Also, overexpression of AHR facilitated cell proliferation and migration via up-regulation of NDRG1, whereas shRNA knockdown of NDRG1 reduced cell growth and motility. In summary, these results showed for the first time that AHR positively regulates NDRG1 transcription through a AHR binding site by hypoxia-mimetic signaling, which may lead to development of a specific therapeutic regime to prevent tumor malignancy under hypoxia.
Citation Format: En-Yu Li, Wei-Yung Huang, Mong-Hsun Tsai, Eric Y. Chuang, Liang-Chuan Lai. Aryl hydrocarbon receptor activates NDRG1 transcription under hypoxia in breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1983. doi:10.1158/1538-7445.AM2015-1983
Abstract 1992: Evidence for modulation of FoxM1 by p21 in ovarian cancer
Authors: Madden Jill , Chien Jeremy 
Published: August 2015

Abstract
The oncogenic transcription factor forkhead box M1 (FoxM1) is overexpressed in many cancers, including 84% of ovarian cancer and plays a role in DNA repair, mitotic checkpoint, cell proliferation, and cancer drug resistance. Similar to Her2 in breast cancer, the constitutive expression of FoxM1 makes it a plausible gene target for novel anti-cancer therapies, but the regulation of FoxM1 has yet to be elucidated. Evidence suggests FoxM1 up-regulation is a result of TP53 mutations, however, no TP53 response element has been found within the FoxM1 promoter, thus there is likely another molecule mediating p53-induced FoxM1 overexpression. We hypothesize that cyclin-dependent kinase inhibitor 1a, p21, is involved in the regulation of FoxM1 by p53 in ovarian cancer. To test this hypothesis, we knocked down p21 expression with siRNA and shRNA in two wild-type p53 cancer cell lines, NCI-H23 and A2780. Knock down of p21 resulted in a mirrored increase in FoxM1 protein level in both cell lines as detected by Western blot. The addition of nutlin-3 (10 μM), a p53 stabilizer, to these p21 knocked down cell lines restored some p21 expression 24 hour post-treatment, which led to a subsequent decrease in FoxM1 levels compared to the corresponding DMSO-treated p21 knock down. These results suggest p21 is a negative regulator of FoxM1 in cancer cell lines. To further investigate this pathway, the same two cancer cell lines were treated with the FoxM1 inhibitor thiostrepton (10 μM) and protein levels were measured over a time course of 48 hours. FoxM1 protein levels were reduced following 8 hours, a time point where p21 protein levels peaked. This finding was further support by qRT-PCR analysis of A2780 ovarian cancer cell mRNA collected 0, 6, 8, 9, 10, 11, and 12 hours following thiostrepton (10 μM) treatment. In this experiment, p21 mRNA levels peaked 6 hours post-treatment, with FoxM1 mRNA levels reduced at 8 hours post-treatment, relative to control. Although thiostrepton has been shown to directly bind and inhibit the transcription of FoxM1, these results suggest that thiostrepton may also induce p21, potentiating FoxM1 inhibition. Thiostrepton has previously been shown to induce cancer cell death and reduce tumor burden, therefore further supporting FoxM1 as a potential drug target as well as encouraging the need to understand regulators involved in this pathway.
Citation Format: Jill Madden, Jeremy Chien. Evidence for modulation of FoxM1 by p21 in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1992. doi:10.1158/1538-7445.AM2015-1992
Abstract 2001: Identification of lactate dehydrogenase A (LDHA) as a potential therapeutic target for prostate cancer radiotherapy
Authors: Hao Jingli , Graham Peter H. , Chang Lei , Ni Jie , Wasinger Valerie , Beretov Julia , Bucci Joseph , Cozzi Paul , Li Yong 
Published: August 2015

Abstract
Introduction: Radiation therapy (RT) is an important treatment option for prostate cancer (CaP) patients at both early and advanced-stage disease. Many CaP patients suffer from relapse and metastasis due to radio-resistance. In this study, we aimed to develop a radio-resistant CaP (CaP-RR) xenograft model, to identify potential protein markers associated with radio-resistance using proteomic approach, and to validate the identified biomarkers in CaP cell lines and animal xenografts.
Methods: Subcutaneous (s.c) CaP animal model was established using PC3-RR and PC3-control CaP cells in NODSCID mice. Tumor xenografts were harvested 5 weeks post cell inoculation and the proteins were extracted. Using LC-MS/MS expression protein profiles from the two groups were created. Statistical analysis was performed using one-way ANOVA for all features. Mascot was employed for peptide identification. Differential protein expressions were identified by re-importing the Mascot data to Progenesis software. The protein pathways and the top KEGG terms were searched against KEGG database using ingenuity software. Selected pathway markers or modulators were validated in CaP-RR cell lines and xenograft tumors using western blotting and immunohistochemistry, respectively. Lactate dehydrogenase A (LDHA) was selected for functional studies including radio-sensitivity, apoptosis and autophagy assays.
Results: We found for the first time that higher levels of vascularity, proliferation, and proteins from the glycolysis pathway are associated with CaP-RR xenograft tumors and that more than two hundred proteins were differentially expressed between CaP-RR and CaP naïve tumor xenografts. In addition, we demonstrated that the increased expressions of glycolysis markers, including LDHA, were certified in both CaP- CaP-RR cell lines and xenograft tumors. Knock-down or inhibition of LDHA combined with RT increase the radiosensitivity in PC3-RR cells, induce more apoptosis and autophagy compared to each single treatment alone.
Conclusions: We have successfully identified protein signatures using a CaP-RR xenograft animal model. The glycolysis pathway protein LDHA is a promising candidate to develop combination therapy to overcome CaP radioresistance.
Citation Format: Jingli Hao, Peter H. Graham, Lei Chang, Jie Ni, Valerie Wasinger, Julia Beretov, Joseph Bucci, Paul Cozzi, Yong Li. Identification of lactate dehydrogenase A (LDHA) as a potential therapeutic target for prostate cancer radiotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2001. doi:10.1158/1538-7445.AM2015-2001
Abstract 2023: MYC amplification and overexpression in metastatic anaplastic thyroid cancer dictates response to therapy
Authors: Yilmaz Emrullah , Russo Marika A. , Orlacchio Arturo , Forde Toni , Di Cristofano Antonio 
Published: August 2015

Abstract
Anaplastic thyroid cancer (ATC) is a very aggressive and lethal cancer with few months of survival from diagnosis. Although less than 2% of all thyroid carcinomas are ATC, it accounts for up to 40% of thyroid carcinoma deaths. TRP53 inactivating mutations and PI3K activation through loss of PTEN, or PIK3CA mutations and amplification are common in ATC. In fact, targeted deletion of Pten and Trp53 in the mouse thyroid results in ATC development.
Using this mouse model, we found that Myc is amplified in 38% (11/29) of [Pten,Trp53]thyr-/− ATCs with distant metastasis, but only in 10% (3/30) non-metastatic ATCs. Conversely Myc was not amplified in any of 15 metastatic follicular thyroid carcinomas developed by Ptenthyr-/− mice. Analysis of human ATCs showed Myc amplification in 17% (3/18) tumors and protein overexpression in 25% of samples in a tissue microarray.
Myc amplification has been shown to be associated with resistance to PI3K targeted therapies in different tumor types. We evaluated the role of Myc in ATC growth and response to therapy using cell lines derived from our [Pten,p53]thyr-/− mouse model.
Myc-amplified cell lines grew faster than cell lines from tumors without Myc amplification both in full medium and under serum deprivation. Myc knockdown resulted in a dramatic decrease in growth rate, especially under serum starvations, suggesting that tumors with Myc amplification are less dependent on growth factors present in the serum. Myc knockdown in Myc-amplified cells completely impaired tumor formation in syngeneic mice.
To evaluate the effect of Myc amplification on drug sensitivity, we screened a panel of drugs on cultured cells. Myc knockdown sensitized ATC cells to PLK1 inhibition with BI6727, PI3K inhibition with BKM120, as well as to doxorubicin and etoposide. Conversely, Myc-amplified cells were more sensitive to carboplatin.
Our results show that Myc amplification is a biomarker for more aggressive and resistant ATCs and that MYC-targeting strategies could be employed to sensitize these tumors to conventional and targeted therapy.
Citation Format: Emrullah Yilmaz, Marika A. Russo, Arturo Orlacchio, Toni Forde, Antonio Di Cristofano. MYC amplification and overexpression in metastatic anaplastic thyroid cancer dictates response to therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2023. doi:10.1158/1538-7445.AM2015-2023
Abstract 2029: Mcph1/Brit1 deficiency promotes genomic instability and tumor formation in a mouse model
Authors: Liang Yulong , Gao Hong , Lin Shiaw-Yih , Goss John A. , Du Chunying , Li Kaiyi 
Published: August 2015

Abstract
MCPH1, also known as BRIT1, has recently been identified as a novel key regulatory gene of the DNA damage response pathway. MCPH1 is located on human chromosome 8p23.1, where human cancers frequently show loss of heterozygosity. As such, MCPH1 is aberrantly expressed in many malignancies, including breast and ovarian cancers, and the function of MCPH1 has been implicated in tumor suppression. However, it remains poorly understood whether MCPH1 deficiency leads to tumorigenesis. Here, we generated and studied both Mcph1−/− and Mcph1−/−p53−/− mice; we showed that Mcph1−/− mice developed tumors with long latency, and that primary lymphoma developed significantly earlier in Mcph1−/−p53−/− mice than in Mcph11+/+p53−/− and Mcph1+/−p53−/- mice. The Mcph1−/−p53−/− lymphomas and derived murine embryonic fibroblasts (MEFs) were both more sensitive to irradiation. Mcph1 deficiency resulted in remarkably increased chromosome and chromatid breaks in Mcph1−/−p53−/− lymphomas and MEFs, as determined by metaphase spread assay and spectral karyotyping analysis. Additionally, Mcph1 deficiency significantly enhanced aneuploidy as well as abnormal centrosome multiplication in Mcph1−/−p53−/− cells. Meanwhile, Mcph1 deficiency impaired double strand break (DSB) repair in Mcph1−/−p53−/− MEFs as demonstrated by neutral Comet assay. Compared with Mcph1+/+p53−/− MEFs, homologous recombination and non-homologous end joining activities were significantly decreased in Mcph1−/−p53−/− MEFs. Notably, reconstituted MCPH1 rescued the defects of DSB repair and alleviated chromosomal aberrations in Mcph1−/−p53−/- MEFs. Taken together, our data demonstrate MCPH1 deficiency promotes genomic instability and increases cancer susceptibility. Our study using knockout mouse models provides convincing genetic evidence that MCPH1 is a bona fide tumor suppressor gene. Its deficiency leading to defective DNA repair in tumors can be utilized to develop novel targeted cancer therapies in the future.
Citation Format: Yulong Liang, Hong Gao, Shiaw-Yih Lin, John A. Goss, Chunying Du, Kaiyi Li. Mcph1/Brit1 deficiency promotes genomic instability and tumor formation in a mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2029. doi:10.1158/1538-7445.AM2015-2029