bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4420: MiR-182 suppresses invadopodia formation and metastasis in non-small cell lung cancer by targeting cortactin
Authors: Li Yongwen , Zhang Hongbing , Liu Hongyu , Chen Jun 
Published: August 2018

Abstract
Metastasis is the leading cause of cancer mortality and is a major hurdle for lung cancer treatment. Invadopodia, which are cancer-specific protrusive structures, play a crucial role in the metastatic cascade through degradation of the basement membrane and surrounding stroma, but the exact mechanism of regulation is not yet fully understood. In this study, we show that cortactin (CTTN), an important component of invadopodia, is upregulated in lung cancer tissues and is a marker of poorer prognosis in human NSCLC. Phorbol 12,13-dibutyrate and hepatocyte growth factor can induce CTTN expression and motility, as well as invadopodia formation in non-small cell lung cancer (NSCLC). MicroRNA-182 (miR-182) suppresses metastasis and invadopodia formation by targeting CTTN in NSCLC. qRT-PCR results showed that CTTN expression was inversely correlated with expression of miR-182. miR-182/CTTN suppresses invadopodia formation of lung cancer cells via suppression of the Cdc42/N-WASP pathway. Furthermore, miR-182 negatively regulates invadopodia function and suppresses extracellular matrix degradation in lung cancer cells by inhibiting CTTN. In conclusion, our results demonstrated that miR-182 targets CTTN in NSCLC and suppresses lung cancer invadopodia formation and thus suppresses lung cancer metastasis, suggesting a therapeutic application of miR-182 in NSCLC.
Citation Format: Yongwen Li, Hongbing Zhang, Hongyu Liu, Jun Chen. MiR-182 suppresses invadopodia formation and metastasis in non-small cell lung cancer by targeting cortactin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4420.
Abstract 4422: miR-125b mediates oral cancer suppression by targeting the antioxidative gene peroxiredoxin like 2A (PRXL2A)
Authors: Chen Yi-Fen , Wei Yun-Yen , Yang Cheng-Chieh , Liu Chung-Ji , Chang Kuo-Wei , Lin Shu-Chun 
Published: August 2018

Abstract
Oral squamous cell carcinoma (OSCC) is a globally prevalent malignancy. The molecular mechanisms of this cancer remain to be elucidated to acquire further interception. Peroxiredoxin like 2A (PRXL2A) was named FAM213A previously, has been reported an antioxidant protein that protects cells from oxidative stress. Our previous study has identified the association between PRXL2A up-regulation in OSCC and the worse prognosis of patients. MicroRNAs (miRNAs) are small non-coding RNAs involved in the modulation of physical or pathological properties. miR-125 family genes drive pluripotent regulation in a wide variety of cancers. In this study, we specified the oncogenic eligibility of PRXL2A and clarified miR-125b as its upstream regulator. Down-regulation of miR-125b was observed in OSCC tumors. Lower miR-125b expression in OSCC tissues defined the worse patient prognosis. Reporter assays validated that PRXL2A as a direct target of miR-125b. Exogenous miR-125b expression resulted in the decreased oxidative stress, increased drug sensitivity, and suppressor activities, which was consistent with the knockout of PRXL2A gene in OSCC cells. That the suppressor activities of miR-125b being rescued by PRXL2A denoted the existence of miR-125b-PRXL2A regulatory axis in OSCC pathogenesis. Knockout of PRXL2A drastically attenuated the tumorigenic potential of OSCC cells. Overall, this study proposes novel clues demonstrating that the down-regulation of miR-125b suppressor underlies the PRXL2A up-regulation in OSCC, and this protects tumor cells from oxidative stress leading to the worse patient survival.
Citation Format: Yi-Fen Chen, Yun-Yen Wei, Cheng-Chieh Yang, Chung-Ji Liu, Kuo-Wei Chang, Shu-Chun Lin. miR-125b mediates oral cancer suppression by targeting the antioxidative gene peroxiredoxin like 2A (PRXL2A) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4422.
Abstract 4423: MiR551b-mediated Oncostatin M signaling in breast cancer
Authors: Geethadevi Anjali , Parashar Deepak , Ragle-Aure Miriam , Nair Bindu , Lu Yiling , Kristensen Vessela N. , You Ming , Sood Anil K. , Mills Gordon B. , Pradeep Sunila , Raghavan Pradeep Chaluvally 
Published: August 2018

Abstract
We have previously demonstrated that an oncogenic microRNA miR551b-3p (also known as miR551b) regulates STAT3 transcription thereby enhancing tumor growth and metastasis in ovarian cancer. Herein, we have identified that Oncostatin M (OSM) is upregulated through STAT3-driven transcription, which plays an important role in promoting migration and invasion of breast cancer cells. The purpose of this study was to evaluate the role of miR551b mediated STAT3 activation and the precise mechanism that regulates OSM-Receptor (OSMR) signaling for breast cancer growth and metastasis. MDA-MB231 cells were either overexpressed or silenced with miR551b and anti-miR551b respectively and the effects on proliferation, migration/invasion (Matrigel transwell assay), wound healing and expression of OSMR and its downstream targets (Western blotting, Quantitative RT-PCR) were assessed. Our data demonstrate that miR551b promoted survival, proliferation, invasion and migration and epithelial to mesenchymal transition (EMT) and spheroid formation of breast cancer cells. Our results also show that miR551b-mediated STAT3 activation upregulated the components of OSMR signaling through elevated expression of OSMR, Interleukin 31 receptor-alpha (IL31RA) and their ligands Oncostatin (OSM) and IL31 thereby inducing phosphorylation of STAT3 for tumor cell proliferation, migration and invasion. Conversely, anti-miR551b reduced the expression of OSMR, IL31R and their ligands OSM and IL31 as well as the phosphorylation of STAT3. Briefly, our results provide the first report indicating that miR551b regulates OSMR expression by activating STAT3 and thereby promoting tumor cell growth and metastasis in breast cancer cells through autocrine feed-forward signaling loop.
A.G, D.P., contributed equally.
Citation Format: Anjali Geethadevi, Deepak Parashar, Miriam Ragle-Aure, Bindu Nair, Yiling Lu, Vessela N. Kristensen, Ming You, Anil K. Sood, Gordon B. Mills, Sunila Pradeep, Pradeep Chaluvally Raghavan. MiR551b-mediated Oncostatin M signaling in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4423.
Abstract 444: ER Stress marker GRP78 is not expressed on ER-/PR-/Her2- human breast cancer cell surface or secreted
Authors: Serrano Jesus E. , Rivera-Ruiz Andrea , Baksi Krishna , Banerjee Dipak K. 
Published: August 2018

Abstract
GRP78 (a Mr 78kDa calcium dependent glucose binding protein) located in ER lumen. It functions as ER chaperone and translocates proteins for glycosylation at the asparagine residue present in the sequon Asn-X-Ser/Thr (i.e., N-linked glycosylation). This important biochemical event is essential for glycoprotein folding and function. When targeted in ER-/PR-/HER2+ breast tumor in athymic nude mice with the N-glycosylation inhibitor tunicamycin, the cancer growth was reduced ~55% in three weeks. Paraffin sections of the tumor exhibited reduced N-glycan level, and reduced angiogenesis but increased GRP78 expression in microvasculature as well as in the tumor tissue (J. Biol. Chem. 286, 29127–29138, 2011). This supported the presence of ER stress. We have now evaluated the effect of tunicamycin on the proliferation of metastatic ER-/PR-/HER2- (MDA-MB-231) and non-metastatic ER+ (MCF-7) human breast cancer cells. Tunicamycin inhibited proliferation of both cells types in a time and dose-dependent manner. Interestingly, GRP78 expression (protein and mRNA) was higher in tunicamycin (1.0 µg/ml) treated MDA-MB-231 and in MCF-7 cells and supported by both Western blotting and qPCR. Since GRP78 is an ER stress marker, so we have followed its intracellular localization by immunofluorescence microscopy after treating the cancer cells with tunicamycin as well as after subjecting them to various stress conditions. We have used unfixed cells and stained with either FITC-conjugated Concanavalin A (Con A), or Texas-red conjugated wheat germ agglutinin (WGA) or with anti-GRP antibody. There were expression of N-glycans but not GRP78. GRP78 however became detectable after permeabilization of cells with a brief exposure to ice-cold methanol. GRP78 was not detected in the conditioned media of the cancer cell but a high level of MMP-1 did. We have therefore, concluded that GRP78 is expressed neither on the outer-leaflet of the (ER-/PR-/HER2-) human breast cancer cells nor it is secreted into the culture media during tunicamycin-induced ER stress. This is obviously, contradicted the current dogma that GRP78 expression on the tumor cell surface interferes with the cancer therapeutic(s) and make them as tumor promoters and not tumor suppressors. Our study, thus, suggests strongly that anti-angiogenic and anti-tumorigenic action of tunicamycin can be modeled to develop next generation cancer therapy, i.e., glycotherapy for treating breast tumor and all other sold tumors. Supported in part by the university funds and NIH/NIMHD G12MD007583 (KB).
Citation Format: Jesus E. Serrano, Andrea Rivera-Ruiz, Krishna Baksi, Dipak K. Banerjee. ER Stress marker GRP78 is not expressed on ER-/PR-/Her2- human breast cancer cell surface or secreted [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 444.
Abstract 446: HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation
Authors: Tigue Megan L. , Kijima Toshiki , Prince Thomas L. , Yim Kendrick H. , Schwartz Harvey , Beebe Kristin , Lee Sunmin , Budzynski Marek A. , Williams Heinric , Trepel Jane B. , Sistonen Lea , Calderwood Stuart , Neckers Len 
Published: August 2018

Abstract
Heat shock factor 1 (HSF1) is an evolutionarily conserved transcription factor that initiates the cytoprotective heat shock response (HSR) and mediates a cancer-specific transcriptional program, which is comprised of over 500 genes and has been associated with poor clinical outcomes. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). The purpose of our study was to describe the interactions between molecular chaperones, such as HSP90 and HSP70, and HSF1 and to determine the mechanism(s) by which HSP90 inhibitors promote the HSR in mammalian cells. Using a combination of techniques including IP-WB, ChIP, and RT-qPCR analysis, we demonstrated that HSP90 binding to HSF1 depends on HSP90 conformation and is only readily visualized for the ATP-dependent, N-domain dimerized chaperone, a conformation rarely sampled by mammalian HSP90. We also showed that ATP-competitive, N-domain targeted HSP90 inhibitors disrupt this interaction and enhance HSF1 phosphorylation, resulting in the increased duration of HSF1 occupancy of the hsp70 promoter and significant prolongation of both the constitutive and heat-induced HSF1 transcriptional activity. While our data do not support a role for HSP90 in sequestering HSF1 monomers to suppress HSF1 transcriptional activity, as has been previously proposed, our findings do identify a noncanonical role for HSP90 in providing dynamic modulation of HSF1 activity by participating in removal of HSF1 trimers from heat shock elements in DNA, thus terminating the heat shock response.
Citation Format: Megan L. Tigue, Toshiki Kijima, Thomas L. Prince, Kendrick H. Yim, Harvey Schwartz, Kristin Beebe, Sunmin Lee, Marek A. Budzynski, Heinric Williams, Jane B. Trepel, Lea Sistonen, Stuart Calderwood, Len Neckers. HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 446.
Abstract 4463: Loss of APC mediates doxorubicin resistance in breast cancer cells
Authors: Stefanski Casey D. , Keffler Kaitlyn , McClintock Stephanie , Prosperi Jenifer R. 
Published: August 2018

Abstract
Resistance to chemotherapy is one of the leading causes of breast cancer related deaths. Understanding the molecular basis for chemoresistance is essential for the advancement of novel therapeutic approaches to ultimately improve patient outcomes. The Adenomatous Polyposis Coli (APC) tumor suppressor is either mutated or hypermethylated in up to 70% of sporadic breast cancer; however, little is known about how loss of APC contributes to chemoresistance. Using the ApcMin/+ mouse crossed to the Polyoma middle T antigen (PyMT) transgenic model, we demonstrated that APC loss decreased cisplatin and doxorubicin-induced apoptosis. We previously showed that loss of APC in MMTV-PyMT;ApcMin/+ cells induced STAT3-activation resulting in an enhanced tumor initiating cell (TIC) population and increased multidrug resistance protein 1 (MDR1) expression. Therefore, we hypothesized that APC loss increased MDR1 activity and decreased doxorubicin-mediated DNA damage, ultimately preventing cell death. Using calcein incorporation, we first demonstrated that APC loss increased MDR1 activity which was normalized to WT control levels by the MDR1 inhibitor, Valspodar. We next showed that MDR1 inhibition in MMTV-PyMT;ApcMin/+ cells could restore doxorubicin-mediated apoptosis to that of MMTV-PyMT;Apc+/+ treated cells. Due to STAT3 inducing MDR1 activity and TIC population, MDR1 inhibition in MMTV-PyMT;ApcMin/+ cells was also shown to reduce the TIC population. In addition, we are investigating the effect of APC loss on DNA damage repair pathways. Preliminary studies have shown decreased γH2AX in MMTV-PyMT;ApcMin/+ cells treated with doxorubicin, suggesting a decrease in DNA damage. Downstream signaling of γH2AX, measured by phosphorylation of ATM, also demonstrated decreased DNA damage with ongoing studies measuring phosphorylation of ATR. Due to APC binding to topoisomerase IIα (topo IIα), a target of doxorubicin, the activity of topo IIα was measured to address whether this decreased DNA damage was attributed to impaired topo IIα activity or decreased intracellular doxorubicin due to increased MDR1 efflux. Future studies will investigate whether MDR1 inhibition in combination with doxorubicin will reduce tumor burden in vivo. Taken together, APC loss mediates doxorubicin resistance via enhanced MDR1 activity and altered DNA damage repair pathways demonstrating the potential use of combination therapy to overcome resistance to chemotherapy.
Citation Format: Casey D. Stefanski, Kaitlyn Keffler, Stephanie McClintock, Jenifer R. Prosperi. Loss of APC mediates doxorubicin resistance in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4463.
Abstract 4464: CPEB-2 is a tumor-suppressor gene in human breast cancer
Authors: Lala Peeyush K. , Tordjman Joshua , Amiri Mehdi , Hasan Asma , Hess David , Majumder Mousumi 
Published: August 2018

Abstract
We found that expression of cyclooxygenase (COX)-2 promotes breast cancer progression by multiple mechanisms, including stimulation of cancer cell proliferation, migration, invasiveness, epithelial-to-mesenchymal transition (EMT), angiogenesis, lymphangiogenesis and induction of stem-like cells (SLC). Through combined gene expression and microRNA microarray analyses of COX-2-transfected MCF-7 cells, we identified two oncogenic miRNAs, miR-526b and miR-655, up-regulated by COX-2. They collectively target 13 tumour suppressor-like genes down-regulated by COX-2, of which Cytoplasmic Polyadenylation Element-Binding Protein -2 (CPEB-2) was the single common target, whose function is unclear in breast cancer. CPEB-2 is known to downregulate mesenchymal transcription factor TWIST1 and translation of HIF1α. CPEB-2 has multiple isoforms (A-F), of which a high B: A isoform ratio was reported to confer anoikis-resistance, a metastatic phenotype, in breast cancer cells. We found that CPEB-2 expression was inversely correlated with COX-2 or the microRNAs miR-526b and miR-655 in breast cancer cell lines; it was very high in a non-tumorigenic mammary epithelial cell line MCF10A.To define its functional roles we knocked out CPEB-2 in MCF10A cells by CRISPR/Cas9-double nickase approach. CPEB-2-KO cells exhibited oncogenic phenotypes in vitro: increased proliferation, migration, invasion, EMT phenotype (decreased E-Cadherin, increased Vimentin, N-cadherin, SNAI1, and ZEB1) and SLC properties (increased spheroid formation and SLC-linked markers). P53 protein was found to be a novel translationally- regulated target of CPEB-2. CPEB-2KO cells, but not wild-type cells, produced lung colonies upon intravenous injection and orthotopic tumors (identified by HLA staining) upon implantation at mammary sites in NOD/SCID/IL2Rϒ-null mice. In human breast cancer tissues, compared to non-tumour breast tissues, isoform A/E of CPEB2 revealed a lower expression in HER2+ breast cancer samples, suggesting that CPEB-2A/E are the tumour-suppressor isoforms. These findings demonstrate that CPEB-2 is a tumour suppressor gene in breast cancer. (Supported by the OICR and the NSERC)
Citation Format: Peeyush K. Lala, Joshua Tordjman, Mehdi Amiri, Asma Hasan, David Hess, Mousumi Majumder. CPEB-2 is a tumor-suppressor gene in human breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4464.
Abstract 447: A novel proteotoxic combination therapy for EGFR+ and HER2+ cancers
Authors: Wang Mengxiong , Ferreira Renan , Law Mary , Yaaghubi Elham , Heldermon Coy , Castellano Ronald , Law Brian 
Published: August 2018

Abstract
EGFR and/or HER2 are frequently overexpressed oncoproteins in HER2+ breast cancer, Triple Negative Breast Cancer (TNBC), and Inflammatory Breast Cancer (IBC). However, EGFR and/or HER2 targeting agents have failed to make major advances in improving survival for these cancer patients, largely because these cancers frequently develop resistance to these drugs. The identification of novel treatment strategies is critically needed. Overexpression of EGFR and/or HER2 presents a severe burden to the secretary pathway, as HER-family proteins EGFR, HER2, HER3 share conserved extracellular cysteine-rich and proline-rich repeats that form numerous disulfide bonds and control cis-trans isomerization in the protein folding processes. We demonstrated that the disulfide bond disrupting Agents (DDAs) selectively killed EGFR+ and/or HER2+ breast cancer cells in vitro and decreased tumor growth of HER2+ cancer in a xenograft mouse model. DDA-dependent anti-cancer actions resulted from downregulation of EGFR/HER2/HER3, induction of AKT dephosphorylation, and activation of Endoplasmic Reticulum (ER) stress. We also investigated a novel proteotoxic combination therapy employing DDAs and Proline Isomerase Inhibitors (PIIs) in treating breast cancers. PIIs potentiated the efficacy of DDAs in downregulating EGFR/HER2/HER3 levels and initiating ER stress, and the combination was highly synergistic in reducing EGFR+ and/or HER2+ breast cancer cell viability. Importantly, the combination of DDAs and PIIs overcame single drug resistance, significantly decreased tumor volumes and increased the survival of xenograft mice. Evidence that the drug combination was effective against metastatic breast cancer cells is also provided.
Citation Format: Mengxiong Wang, Renan Ferreira, Mary Law, Elham Yaaghubi, Coy Heldermon, Ronald Castellano, Brian Law. A novel proteotoxic combination therapy for EGFR+ and HER2+ cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 447.
Abstract 4470: Loss of ARL6IP4 induces the epithelial mesenchymal transition in breast cancer metastasis by transcriptionally phosphorylating NF-kB
Authors: Park Mi Kyung , Jang Ji Yun , Byun Hyun Jung , Kim Hyun Ji , Lee Ho , Lee Chang Hoon 
Published: August 2018

Abstract
The epithelial mesenchymal transition EMT is the major mechanism involved in cancer metastasis. During EMT, epithelial cells lose cell-cell adhesions to gain mesenchymal-like properties, such as increased invasive abilities. The function of ARL6IP4 in the EMT of breast cancers has not yet been studied. Here we show that the ARL6IP4 controls EMT in breast cancer metastasis. we demonstrate that the role of ARL6IP4 by analysis of ARL6IP4 conditional knockout animals, various in vitro and in vivo models of EMT and metastasis, a mouse mammary tumor virus-polyoma middle T antigen (MMTV-PyMT) model of breast cancer metastasis. We identified that loss of ARL6IP4 phosphorylated of nuclear factor-κB (NF-κB) by increasing the expression of the SNAIL and ZEB1 EMT transcription factors (EMT-TFs). Taken together, our findings establish that ARL6IP4 is a potential tumor suppressor by regulation the phosphorylation of NF-κB.
Citation Format: Mi Kyung Park, Ji Yun Jang, Hyun Jung Byun, Hyun Ji Kim, Ho Lee, Chang Hoon Lee. Loss of ARL6IP4 induces the epithelial mesenchymal transition in breast cancer metastasis by transcriptionally phosphorylating NF-kB [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4470.