bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4213: Evaluation of LMTK3 expression and tumor phenotype in estrogen-dependent colorectal cancer
Authors: Magturo Sybil , Giamas Georgios , Mallick Snay , Layton Austin , Stebbing Justin , Lenz Heinz-Josef , LaBonte Melissa J. 
Published: May 2015

Abstract
Background: Incompatible physiology between genders influences development and progression of colorectal cancer (CRC). It is postulated that improved survival of women with CRC may be due to exogenous estrogen exposure. A recent study used the age of 50 as a surrogate for menopause, evaluating survival in two age groups: women ≥50 and ≤50. It was observed that women ≤50 had a survival advantage that was contributed to protection by estrogen- a mechanism lost in menopause; with no significant difference found in men. Lemur tyrosine kinase 3 (LMTK3) was recently identified, that when in association with an estrogen receptor (ER) α modulator increased growth, progression, and altered resistance to endocrine therapy was observed in breast cancer. The ER family (ERα and ERβ) exerts contrasting actions of estrogen on different target tissues, where ERβ is the dominant receptor expressed in the gastrointestinal tract. The different ER distribution between breast and colon cancer led to the hypothesis that LMTK3 overexpression should stabilize ERβ and decrease tumorigenesis in CRC. Methods: CRC cell lines were characterized for LMTK3 mRNA (qRT-PCR) and protein expression (Western blot) in both transfected and non-transfected cell lines. Overexpression of LMTK3 was achieved utilizing pCMV6-XL4-LMTK3. Overexpressing LMTK3 CRC cells were evaluated for alterations to cell viability by MTT, colony formation (CFAs), invasion assays and chemosensitivity to 5-Fluororuacil, oxaliplatin, and tamoxifen. Results: CRC cell lines demonstrated a range of LMTK3, ERα and ERβ mRNA and protein expression. Caco-2, HCT116 and LoVo cells demonstrated estrogen sensitivity as evidenced by treatment with ER antagonist, tamoxifen. CFA demonstrated that the presence of estrogen plus overexpression of LMTK3 decreased cell viability by 27, 28 and 36% in Caco2, HCT116 and LoVo cells respectively, had limited impact on chemosensitivity, and decreased their ability to invade. Conclusion: This study demonstrates that estrogen mediated cell signaling and LMTK3 play an important role in decreasing CRC tumorigenesis. Further studies are underway to better understand estrogen and LMTK3's role in CRC.
Citation Format: Sybil Magturo, Georgios Giamas, Snay Mallick, Austin Layton, Justin Stebbing, Heinz-Josef Lenz, Melissa J. LaBonte. Evaluation of LMTK3 expression and tumor phenotype in estrogen-dependent colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4213. doi:10.1158/1538-7445.AM2014-4213
Abstract 4215: SPAG5 upregulation predicts poor prognosis of cervical cancer patients and alters the sensitivity of Taxol treatment via mTOR signaling pathway
Authors: Yuan Lin-Jing , Zhang Lan , Zhou Yun , Zheng Min 
Published: May 2015

Abstract
Our previous work found SPAG5 to be upregulated in pelvic lymphnode metastasis positive cervical cancer, the aim of the present study was to examine the role of SPAG5 in proliferation and tumorigenicity of cervical cancers, and its clinical significance in tumor progression. By detecting SPAG5 expression in cervical cancer patients and exploring cervical cancer cell function with SPAG5 downregulation in vitro, our results revealed that SPAG5 upregulated in tumor tissue compared with paired adjacent noncancerous tissues, and the upregulation of SPAG5 in tumor tissues also indicated poor disease free survival which was also an independent prognostic indicator of cervical cancer patients. In vitro study demonstrated that SPAG5 downregulation inhibited cell proliferation and growth significantly by G2/M arrest and apoptosis induction, and also hindered cell migration and invasion. Further study showed different sensitivity of cervical cells to different doses of Taxol treatment under SPAG5 downregulation, which is correlated with mTOR signaling pathway activity. In this study, we demonstrated that SPAG5 upregulation related to poor prognosis of cervical cancer patients, and SPAG5 was a regulator of mTOR activity during Taxol treatment in cervical cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Lin-Jing Yuan, Lan Zhang, Yun Zhou, Min Zheng. SPAG5 upregulation predicts poor prognosis of cervical cancer patients and alters the sensitivity of Taxol treatment via mTOR signaling pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4215. doi:10.1158/1538-7445.AM2014-4215
Abstract 4218: Combined effect of COX2 genotype, ER status, body constitution, and treatment on risk of early events in breast cancer patients
Authors: Markkula Andrea , Simonsson Maria , Ingvar Christian , Rose Carsten , Jernström Helena 
Published: May 2015

Abstract
Aim: The aim of the present study was to investigate the impact of the COX2 rs5277 polymorphism on early events and treatment response in relation to tumor ER-status and to determine whether any effect is modified by body constitution.
Background: The synonymous COX2 rs5277 polymorphism (306G&gt;C, V102V) has been directly linked to several cancers associated with inflammation. Breast cancer patients with tumors expressing COX-2 have a shorter disease-free survival. It is currently unclear whether the rs5277 genotype is correlated with tumor COX-2 expression. Tumor COX-2 expression may have contrasting effects on breast cancer tumors depending on the tumor's estrogen receptor (ER) status. It has been associated with increased estrogen levels in ER-positive tumors and Akt-pathway activation in ER-negative tumors.
Methods: The present study is based on data collected from 634 patients initiating treatment between October 2002 and October 2008. Risk of early events was assessed for 570 rs5277-genotyped patients. Body measurements and questionnaires were obtained at the pre-operative visit. Clinical data, patient-, and tumor-characteristics were obtained from questionnaires, patients' charts, population registries, and pathology reports.
Results: Among all patients, 70.1% were GG-carriers, 27.5% were GC-carriers, and 2.4% were CC-carriers. Median follow-up was 5.1 years. Median age was 59.6 years (range 25-99 years). No association was seen between the G/G genotype and risk of early events in patients with ER-positive tumors, but this genotype conferred an over 4-fold increased risk in patients with ER-negative tumors (Pinteraction=0.015). G/G-carriers with a larger breast volume who had received chemotherapy had a 9-fold risk of early events irrespective of ER-status. C-allele carriers with ER-positive tumors who had a larger breast volume and had received endocrine-therapy had a 2-fold increased risk of early events.
Conclusion: COX2 genotype, body constitution, and ER-status had a combined effect on the risk of early events and treatment response. The high risk for early events in certain subgroups of patients suggests that COX2 genotype in combination with body measurements may provide a tool for identifying patients in need of more personalized treatment.
Citation Format: Andrea Markkula, Maria Simonsson, Christian Ingvar, Carsten Rose, Helena Jernström. Combined effect of COX2 genotype, ER status, body constitution, and treatment on risk of early events in breast cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4218. doi:10.1158/1538-7445.AM2014-4218
Abstract 4219: miR-34a, miR-93 and miR-200c - novel molecular regulators of osteosarcoma dormancy
Authors: Tiram Galia , Ferber Shiran , Ofek Paula , Shomron Noam , Udagawa Taturo , Aviel-Ronen Sarit , Barshack Iris , Satchi-Fainaro Ronit 
Published: May 2015

Abstract
There is an increasing interest in elucidating the mechanisms of the earlier stages in tumor progression, the point at which a dormant tumor acquires the ability to grow and metastasize. Although the tumor dormancy phenomenon has important implications for early detection and treatment of cancer, its biology and genetic characteristics are poorly understood. MicroRNAs (miRs), small non-coding RNA molecules which regulate gene expression at the post-transcriptional level, are emerging as key regulators in physiological and pathological processes, including tumorigenesis. We hypothesized that specific miRs may also play a key role in the regulation of tumor dormancy and the “angiogenic switch”. We therefore established a pair of cell lines that generate dormant avascular or fast-growing angiogenic osteosarcomas in SCID mice (Saos-2-D and Saos-2-E respectively). Although these cells share similar growth rate in vitro, when inoculated into mice, Saos-2-E cells generate vascularized and palpable tumors within one month, while Saos-2-D cells remain avascular and non-palpable for a year.
Following our hypothesis, miR arrays of Saos-2-D and Saos-2-E cells were performed. Several miRs that were differentially-expressed in the dormant versus fast-growing-tumor-generating cells were selected for further evaluation. Out of those miRs, miR-34a, miR-93 and miR-200c, when administered complexed with a polymeric nanocarrier, reverted several tumor cell lines forming fast-growing tumors to a dormant non-angiogenic phenotype, both in vitro and in vivo. We therefore propose that these three miRs play a role in the switch from dormancy to progressive disease in human osteosarcoma tumors. Uncovering new molecular targets involved in the tumor dormancy phenomenon could provide important tools for novel dormancy-directed tumor therapy strategies.
Citation Format: Galia Tiram, Shiran Ferber, Paula Ofek, Noam Shomron, Taturo Udagawa, Sarit Aviel-Ronen, Iris Barshack, Ronit Satchi-Fainaro. miR-34a, miR-93 and miR-200c - novel molecular regulators of osteosarcoma dormancy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4219. doi:10.1158/1538-7445.AM2014-4219
Abstract 4220: A cell-penetrating nucleolytic lupus autoantibody damages DNA and is toxic to BRCA2-deficient cancer cells
Authors: Noble Philip W. , Young Melissa R. , Weisbart Richard H. , Hansen James E. 
Published: May 2015

Abstract
Identification of therapeutic agents that are more toxic to malignant cells than normal cells is a key goal in cancer research. Many tumor cells harbor genetic defects that distinguish them from normal cells, and some of these defects have the potential to be exploited in the development of targeted therapies for cancer. Cancer cells with defects in DNA repair are highly susceptible to DNA-damaging agents, but delivery of therapeutic agents into cell nuclei can be challenging. A subset of lupus autoantibodies is associated with nucleolytic activity, and some of these antibodies are capable of nuclear penetration. We hypothesized that such antibodies might be capable of damaging DNA in cell nuclei and therefore have potential as therapeutic agents targeted towards DNA repair-deficient malignancies, such as tumors that are BRCA2-deficient. To test this hypothesis we screened a panel of cell-penetrating lupus autoantibodies for nucleolytic activity, and we identified 5C6 as an antibody of interest. 5C6 catalyzes degradation of single and double-stranded DNA in vitro and induces phospho-H2AX formation in BRCA2-deficient cells. When tested on a matched pair of BRCA2-proficient and deficient cancer cells, 5C6 selectively suppressed the growth of and was significantly more toxic to the BRCA2-deficient cells. These findings demonstrate the potential utility of 5C6 in targeted therapy for DNA repair-deficient malignancies and strengthen the rationale for studies of additional lupus autoantibodies in order to identify the best candidates for development as therapeutic agents. In addition, the toxicity of 5C6 for BRCA2-deficient cells provides further support for the hypothesis that some lupus autoantibodies contribute to the unusual cancer risk profile associated with systemic lupus erythematosus.
Citation Format: Philip W. Noble, Melissa R. Young, Richard H. Weisbart, James E. Hansen. A cell-penetrating nucleolytic lupus autoantibody damages DNA and is toxic to BRCA2-deficient cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4220. doi:10.1158/1538-7445.AM2014-4220
Abstract 4222: Targeting PI3K and mTOR with BEZ235, a dual inhibitor, is efficacious in trastuzumab refractory and HER2+/PIK3CA-mutated breast cancer models
Authors: Williams Casey , Sun Yuliang , Carlson Jennifer , Leyland-Jones Brian , Dey Nandini , De Pradip 
Published: May 2015

Abstract
Background: PI3K pathway activation is a common event in HER2+ breast cancer (BC) either through inactivation of the tumor suppressor gene, PTEN, or activation of PIK3CA. This PIK3CA mutation leads to an oncogenic activity of the PI3K pathway and contributes to therapeutic resistance to trastuzumab (T). The PI3K pathway inhibitor is therefore an attractive drug for HER2+ BC, especially in T-resistant and PIK3CA mutated conditions. Methodology: Here we have studied the in vitro and in vivo effects of BEZ235 in HER2+/T-sensitive (BT474), HER2+/T-resistant (BT474HerR) and HER2+/PIK3CA (HCC1954) mutated models. We assessed in vitro anti-proliferative and activation status of the PI3K-AKT-mTOR signaling pathway following BEZ235 treatment in HER2+ BC cell lines. We next evaluated the impact of BEZ235 on tumor growth and angiogenesis using xenograft models. Results: 1) BEZ235 inhibited downstream activation of the PI3K signaling pathway effectors, p-AKT (Ser473, The308), p-P70S6K, p-S6RP and p-4EBP1, 2) the anti-proliferative activity of BEZ235 was observed by 3D-ON-TOP clonogenic assay, 3) consistent with anti-proliferative effects of BEZ235, the proportion of cells in the G1 phase of the cell cycle increased in all three cell lines with a concomitant decrease in the S phase of their treatment with BEZ235, 4) the initiation of apoptotic activity (annexin V) of BEZ235 was significantly superior to that of RAD001, an allosteric inhibitor of mTOR, and 5) in the HER2+/T-sensitive, HER2+/T-resistant and HER2+/PIK3CA mutated BC xenograft models, BEZ235 inhibited PI3K signaling and had potent anti-tumor activity. Along with its anti-tumor effect, BEZ235 effectively decreased tumor angiogenesis (tumor micro-vessel density via CD31 staining). These inhibitions were more pronounced when BEZ235 was combined with T. Conclusions: BEZ235 inhibits the PI3K-AKT-mTOR signaling pathway and results in anti-proliferative and anti-tumor activity in HER2+ breast cancer cells with both wild type and mutated PIK3CA.
Citation Format: Casey Williams, Yuliang Sun, Jennifer Carlson, Brian Leyland-Jones, Nandini Dey, Pradip De. Targeting PI3K and mTOR with BEZ235, a dual inhibitor, is efficacious in trastuzumab refractory and HER2+/PIK3CA-mutated breast cancer models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4222. doi:10.1158/1538-7445.AM2014-4222
Abstract 4231: Enhanced antitumor efficacy of T-DM1 in combination with pertuzumab in HER2-positive breast cancer models
Authors: Sun Yuliang , Dey Nandini , Carlson Jennifer , Brammer Melissa , De Pradip , Leyland-Jones Brian 
Published: May 2015

Abstract
Background: The HER2 oncogene is amplified in approximately 20-25% of human breast cancers and is a well established therapeutic target. HER2-targeted therapy by trastuzumab (T) has become increasingly important for treating HER2+ breast cancers, and following the EMILIA trial, T-DM1 is expected to serve as a suitable alternative to trastuzumab. Pertuzumab (P), a HER2 targeted monoclonal antibody that prevents HER2 dimerization, showed progression-free survival when used with trastuzumab and docetaxel on HER2+ metastatic breast cancer (CLEOPATRA trial). In this preclinical study, we investigated the effect of combining T-DM1 and P on xenografted HER2+ breast tumors.
Methodology: Growth inhibition, apoptosis, and antitumor efficacy were examined using the 3D-ON-TOP assay, annexinV staining and mouse xenografts respectively, in BT474 (T- sensitive), BT474HR (T-resistant) and HCC1954 (PIK3CA mutated) breast cancer cell lines.
Results: Treatment of HER2-overexpressing tumor cells (T-sensitive, T-resistant and PIK3CA mutant) in vitro with T-DM1 plus pertuzumab resulted in synergistic inhibition of cell proliferation (3D-ON-TOP and 2D clonogenic assays) and induction of apoptotic cell death (annexinV positive cells). The combination (T-DM1+P) also inhibited p-AKT (Ser473 and Thr308) in HER2-overexpressing cells. T-sensitive and T-resistant xenografts regressed completely after 6 weeks of therapy with T-DM1 plus P whereas either single agent inhibited tumor growth partially in both groups. Mice with HCC1954 (HER2+/PIK3CA mutated) xenograft treated with the same combination exhibited significant tumor growth inhibition when compared with vehicle treated mice after 6 weeks of treatment. Conclusions: Our in vitro and in vivo data clearly demonstrated that dual-targeting HER2 with a combination of T-DM1 plus P was highly efficacious both in HER2+/T-resistant and HER2+/PIK3CA mutated xenograft models.
Citation Format: Yuliang Sun, Nandini Dey, Jennifer Carlson, Melissa Brammer, Pradip De, Brian Leyland-Jones. Enhanced antitumor efficacy of T-DM1 in combination with pertuzumab in HER2-positive breast cancer models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4231. doi:10.1158/1538-7445.AM2014-4231
Abstract 4237: Antitumor activity of 2-hydroxycinnamaldehyde against human colorectal cancer cells is mediated by the Wnt/β-catenin signaling pathway
Authors: Kim Won Kyung , Oh Jedo , Bae Song Yi , Song Jayoung , Shin Yoonho , Choi Tae Joon , Jeong Eun Ju , Park So Hyun , Jang Eun Jeong , Kang Ji In , Park Hyen Joo , Hong Ji-Young , Lee Min Ai , Chung Hwa-Jin , Lee Sang Kook 
Published: May 2015

Abstract
The antiproliferative and antitumor activities of 2-hydroxycinnamaldehyde (1), a phenylpropanoid isolated from the bark of Cinnamomum cassia , were investigated using human colorectal cancer cells. Compound 1 exhibited antiproliferative effects in HCT116 colon cancer cells, accompanied by modulation of the Wnt/β-catenin cell signaling pathway. This substance was found also to inhibit β-catenin/T-cell factor (TCF) transcriptional activity in HEK293 cells and HCT116 colon cancer cells. Further mechanistic investigations in human colon cancer cells with aberrantly activated Wnt/β-catenin signaling showed that 1 suppressed significantly the binding of β-catenin/TCF complexes to their specific genomic targets in the nucleus and led to the down-regulation of Wnt target genes such as c-myc and cyclin D1. In an in vivo xenograft model, the intraperitoneal administration of 1 (10 or 20 mg/kg body weight, three times/week) for four weeks suppressed tumor growth in athymic nude mice implanted with HCT116 colon cancer cells significantly, without any apparent toxicity. In an ex vivo biochemical analysis of the tumors, compound 1 was also found to suppress Wnt target genes associated with tumor growth including β-catenin, c-myc, cyclin D1, and survivin. The suppression of the Wnt/β-catenin signaling pathway is a plausible mechanism of action underlying the antiproliferative and antitumor activity of 1 in human colorectal cancer cells (Acknowledgements: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MEST) No. 20120004939)
Citation Format: Won Kyung Kim, Jedo Oh, Song Yi Bae, Jayoung Song, Yoonho Shin, Tae Joon Choi, Eun Ju Jeong, So Hyun Park, Eun Jeong Jang, Ji In Kang, Hyen Joo Park, Ji-Young Hong, Min Ai Lee, Hwa-Jin Chung, Sang Kook Lee. Antitumor activity of 2-hydroxycinnamaldehyde against human colorectal cancer cells is mediated by the Wnt/β-catenin signaling pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4237. doi:10.1158/1538-7445.AM2014-4237
Abstract 4243: EGFR inhibition causes growth delay and induces apoptosis in HPV-positive head and neck cancer
Authors: Law Alexandra D. Torres , Blitzer Grace C. , Smith Molly A. , Armstrong Eric A. , Kimple Randall J. 
Published: May 2015

Abstract
Purpose: Cetuximab, a monoclonal antibody inhibiting the epidermal growth factor receptor (EGFR), is approved for use in the treatment of head and neck cancer (HNC). However, studies of cetuximab were performed with HPV-negative cells, clinical trials were performed without regard to HPV status, and current studies on HPV+ HNC treatment with cetuximab are contradicting. This study was performed to determine whether HPV+ HNC responds to cetuximab and to examine the mechanisms through which cetuximab affects HPV+ HNC.
Methods: Four HPV+ cell lines were assessed for EGFR expression by immunoblot. Sensitivity to cetuximab was tested by examining cell proliferation and colony formation. Apoptosis was measured by caspase activation, flow cytometry for Annexin V, and immunoblot. Cell cycle was assessed by immunoblot and flow cytometry for propidium iodide stained cells. HPV+ HNC subcutaneous flank cell line xenografts and patient-derived xenografts were placed in immunocompromised mice treated with cetuximab, tumor size was measured twice weekly.
Results: Cetuximab treatment resulted in significant delay in cell proliferation and significant decrease in colony formation. Cetuximab caused an increase in apoptosis in all methods measured. Also, as previously seen in HPV- cell lines, cetuximab resulted in a G1 cell cycle arrest. Using both cell line and patient-derived xenograft models of HPV+ HNCs, cetuximab resulted in significant tumor growth delay (median time to tumor quadrupling: 15 vs. 24 days, and 42 vs. 89 days, respectively).
Conclusions: Epidermal growth factor receptor inhibition by cetuximab is effective in slowing proliferation and inducing apoptosis in HPV+ HNC. The proposed mechanism of action appears to be similar to that shown in HPV- HNC. These results suggest that cetuximab may play a role in the management of patients with HPV+ HNC.
Citation Format: Alexandra D. Torres Law, Grace C. Blitzer, Molly A. Smith, Eric A. Armstrong, Randall J. Kimple. EGFR inhibition causes growth delay and induces apoptosis in HPV-positive head and neck cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4243. doi:10.1158/1538-7445.AM2014-4243