bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3258: Breast Metastasis Suppressor 1 (BRMS1) phosphorylation appears necessary for metastasis suppressor activity
Authors: Contreras Lellys M. , Sarcevic Boris , Pounds Keke M. , Welch Danny R. 
Published: August 2015

Abstract
Breast cancer is the most common cancer among women worldwide. BRMS1 is a metastasis suppressor that suppresses metastasis without significantly affecting the growth of a primary tumor. BRMS1 contains two coiled-coil motifs important for protein-protein interactions and two putative nuclear localization sequences (NLS - aa198-205 (NLS1) and aa239-245 (NLS2)) and one nuclear export signal which appear to mediate nuclear-cytoplasmic shuttling. Although NLS2 is not necessary for active transport into the nucleus, it is required for metastasis suppression (PMC3563580). A serine immediately upstream of NLS2 (S237) can be phosphorylated by cdk2 (PMC3037622). Therefore, we hypothesized that NLS2 and adjacent amino acids are critical mediators of metastasis suppression. To test this hypothesis, NLS2 (aa231-248) epitope-tagged with HA and GST was transduced into metastatic MDA-MB-231 and -435 breast carcinoma cells expressing green fluorescent protein and stable colonies were selected. BRMS1S237A-expressing MDA-MB-231 cells were no longer metastasis suppressed, suggesting a critical role for phosphorylation of BRMS1 in its metastasis suppressor activity. Studies are underway with full-length BRMS1S237D (phosphomimetic) as well as expression with truncated wild-type NLS2 and mutant (NLS2wt/S237A/S237D) to test whether the BRMS1 phosphorylation or the NLS2 domain itself is critical for metastasis suppressor activity. Support: CA87728, CA134981, P30-CA168524, Natl Fndn Cancer Res, Komen SAC11037, KS Bioscience Auth, NHMRC
Citation Format: Lellys M. Contreras, Boris Sarcevic, Keke M. Pounds, Danny R. Welch. Breast Metastasis Suppressor 1 (BRMS1) phosphorylation appears necessary for metastasis suppressor activity. [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 3258. doi:10.1158/1538-7445.AM2015-3258
Abstract 3265: Thrombopoietin and megakaryocytes in breast cancer metastasis to bone
Authors: Jackson Walter , Mastro Andrea M. , Sosnoski Donna M. 
Published: August 2015

Abstract
Bone is one of the preferred sites for breast cancer cells to metastases. Once patients are diagnosed with skeletal metastases, the relative five-year survival rate falls from 90% to less than16%. Thrombocytosis is a sign of poor prognosis for survival, and thromboembolisms are one of the leading causes of death in all cancers patients. These conditions are due to high numbers and/or high platelet activity. Megakaryocytes (MKs) are responsible for platelet production, but also play a role in bone metabolism and skeletal homeostasis.
We had determined in two mouse models of experimental metastasis (MDA-MB-231 in athymic mice, and 4T1.2 in Balb/c mice), that bone metastasis was associated with increased numbers of MKs. Under normal conditions MKs represent less than 1% of the total bone marrow cell population, but after analysis of the femurs of the mice with metastasis, we found at least a two-fold increase in the numbers of MKs present in the bone marrow in the MDA-MB-231mice. The Balb/c mice injected in the mammary glands with mouse 4T1.2 cells showed a four-fold increase in MKs in the spleen (extrameduallary hematopoiesis). Therefore we hypothesized that increased megakaryocytosis was linked to metastasis, and that decreasing the number of MKs would decrease metastasis. We transferred a thrombopoietin (TPO) expression deletion mutation to a Balb/c background and inoculated the mice with 4T1.2 cells. These TPO -/- mice showed approximately a 90% decrease in bone marrow MKs compared to the wild type mice. The numbers of blood platelets was also decreased by 90%. We tested our hypothesis by inoculation of 4T1.2LUC cells into the mammary gland, and then followed the course of the cancer and metastasis by luciferase imaging. Contrary to our hypothesis the TPO -/- mice developed metastasis to the bone more rapidly than the heterozygotes or wild type mice. Literature suggests that platelets interact with tumor cells to contribute to hematogenous metastasis and angiogenesis. In the TPO-/- mice with very few platelets, metastasis was more aggressive and developed more rapidly than in the wild type or the heterozygote mice. The next step will be to separate the role of the megakaryocytes from the platelets.
This work was sponsored by the U.S. Army Medical Research and Materiel W81XWH-10-1-0253
Citation Format: Walter Jackson, Andrea M. Mastro, Donna M. Sosnoski. Thrombopoietin and megakaryocytes in breast cancer metastasis to bone. [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 3265. doi:10.1158/1538-7445.AM2015-3265
Abstract 3289: Skeletal consequences of bone resorption inhibitors (zoledronic acid and RANKL blocking antibody) injections during growth: mouse strain disparities and synergic effect
Authors: Lezot Frederic P. , Navet Benjamin , Choi YongWon , Yagita Hideo , Berdal Ariane , Mueller Christopher G. , Redini Francoise , Heymann Dominique 
Published: August 2015

Abstract
Abstract
Background: High doses of bone resorption inhibitors are currently evaluated for the treatment of malignant primary bone tumors. The impact of such an intensive treatment on growing skeleton is a critical question in the context of pediatric oncology.
Methods: Protocols adapted from pediatric treatments were developed for mice (a total of 4 or 5 injections of Zoledronic acid (50 μg/kg) or IKK-22.5 antibody (50 μg/injection) every two or three days). Their impact on tibias, skull bones and teeth growth was analyzed by micro-CT and histology up to 3 months after the last injection. Potential disparities between mouse strains were evaluated using both CD1 and C57BL/6J mice, as was the possible synergic effect of the two inhibitors.
Results: In both mouse strains, bone resorption inhibitors administrations induced a transient delay of tibia and skull bone growth. Indeed, three months after the last injection all bone parameters were back to normal. Regarding tooth eruption and root elongation, both were severely impaired in C57BL/6J mouse whatever the inhibitor considered while in CD1 mouse highly more important doses are necessary to observe similar effects. Combination of both inhibitors, at half-doses in CD1 mouse, induced severe delay of tooth eruption demonstrating the existence of synergic effect between the two inhibitors.
Conclusions: In mouse, high doses of bone resorption inhibitors disturbed teeth eruption and elongation, and delayed tibias and skull bone formation. Difference of sensitivity to these inhibitors was observed between mouse strains which understanding will require further studies. A synergic effect was also observed for these inhibitors. In human, similar treatments may impact the permanent teeth eruption. These observations are crucial for the follow-up of pediatric patients treated with high doses of bone resorption inhibitors in ongoing European and American protocols.
Citation Format: Frederic P. Lezot, Benjamin Navet, YongWon Choi, Hideo Yagita, Ariane Berdal, Christopher G. Mueller, Francoise Redini, Dominique Heymann. Skeletal consequences of bone resorption inhibitors (zoledronic acid and RANKL blocking antibody) injections during growth: mouse strain disparities and synergic effect. [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 3289. doi:10.1158/1538-7445.AM2015-3289
Abstract 3308: Enhanced expression of galectin-3 isassociated with the alternative activation of macrophages and development oflung fibrosis following radiation
Authors: Zhao Weiling , Zhang Jing-Hua , Lopes Ingrid J. 
Published: August 2015

Abstract
Radiotherapy is a major treatment approach to non-operable lung cancer patients. Unfortunately, radiation-induced lung injury occurs in 5-20% of lung cancer patients following radiotherapy. Radiation-induced lung fibrosis contributes to an increased risk of death or a decreased quality of life.
The mechanism(s) for the development of radiation-induced lung fibrosis is not fully understood, and no interventions to prevent/ameliorate it have proven successful. Macrophages are the first line of defense for airways and alveolar surfaces and play a key role in the initiation and orchestration of inflammatory responses. Two distinct macrophage subsets have been identified; classically activated macrophages (M1) and alternatively activated macrophages (M2).
Increased numbers of activated M2 macrophages have been seen in human fibrotic conditions and rodent models of fibrosis. However, the mechanism(s) driving the persistent activation of M2 macrophages and how this leads to the development of fibrosis remains undefined. Recent studies indicate that galectin-3 (gal-3) is potentially a key regulator of M2 macrophage activation; inhibition of gal-3 expression prevents M2 macrophage activation. In this paper, we show elevated numbers of Ym-1 positive alveolar macrophages in the irradiated lung. Increased expression of gal-3 cells was found in the fibrotic lung, which was associated with fibrotic lesions. M2 macrophages were the majority of cells that expressed gal-3.
In our in vitro studies, we found that knocking-down gal-3 using Mission lentiviral transduction particles prevented radiation-induced increases in the expression of YM-1 in Raw 264.7 macrophage. Mouse recombinant gal-3 stimulated mouse lung fibroblast cell proliferation and expression of α-SMA. These data suggest that gal-3 appears to regulate alternative activation of M2 macrophage and play an important role in the development of radiation-induced lung injury.
Citation Format: Weiling Zhao, Jing-Hua Zhang, Ingrid J. Lopes. Enhanced expression of galectin-3 isassociated with the alternative activation of macrophages and development oflung fibrosis following radiation. [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 3308. doi:10.1158/1538-7445.AM2015-3308
Abstract 3309: Co-inhibition of ALK and EGFR and/or c-MET on cell growth and response to radiation in ALK-positive NSCLC cells
Authors: Li Chunrong , Huang Shyhmin , Ma Fang , Armstrong Eric A. , Francis David , Werner Lauryn , Harari Paul M. 
Published: August 2015

Abstract
ALK (anaplastic lymphoma kinase), EGFR (epidermal growth factor receptor) and c-MET are molecular drivers for a subset of non-small cell lung cancers (NSCLC). Approximately 4-7% of NSCLCs carry the EML4-ALK chromosomal rearrangement. We identified overexpression of EGFR and c-MET in EML4-ALK-positive NSCLC cell lines H3122 and H2228. ALK, EGFR, and c-MET may function cooperatively to modulate tumor growth, stress response, and survival in EML4-ALK-positive cells and co-inhibition may favorably impact tumor control. We therefore investigated the effects of co-inhibition of ALK and EGFR or c-MET on cell survival and response to radiation in EML4-ALK-positive NSCLC cells.
Compared with ALK-negative cell lines (H226, A549 and H520), the ALK-positive cell lines (H3122, H2228) were highly sensitive to the ALK inhibitors crizotinb, ceritinib and alectinib, although with differing sensitivity to radiation. Crizotinib, ceritinib and alectinib sensitized H3122 and H2228 to radiation, as evaluated by clonogenic assay. However, knockdown of ALK by siRNA in H3122 and H2228, or overexpression of EML4-ALK in NIH-3T3 cells, had only moderate effects on radiosensitivity. Simultaneous knockdown of ALK and MET, or ALK and EGFR, increased radiosensitivity as assessed by clonogenic survival in H3122 and H2228 cells, while also increasing inhibitory effects on cell growth and proliferation. These results were confirmed in cells treated with the combination of ceritinib and su11274 (c-MET inhibitor) or with ceritinib and erlotinib (EGFR inhibitor). We further assessed the impact of drug alone or in combination with radiation on cell cycle, cell survival and DNA damage repair pathways. To further evaluate ALK function in the cellular response to radiation in NSCLC, we are developing EML4-ALK stable expression cell lines. Evaluation of drug-radiation interactions in xenograft model systems are also under consideration.
These data indicate that co-inhibition of ALK and EGFR or c-MET can enhance growth inhibitory effects in ALK-positive cells and augment radiosensitivity in-vitro, suggesting the potential value for ALK inhibitors combined with EGFR/c-MET-targeting for therapeutic benefit in ALK-positive NSCLC patients with or without radiation.
Citation Format: Chunrong Li, Shyhmin Huang, Fang Ma, Eric A. Armstrong, David Francis, Lauryn Werner, Paul M. Harari. Co-inhibition of ALK and EGFR and/or c-MET on cell growth and response to radiation in ALK-positive NSCLC 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 3309. doi:10.1158/1538-7445.AM2015-3309
Abstract 3331: Gene expression profiling after radiation in human breast cancer specimens and breast cancer cell lines
Authors: Siamakpour-Reihani Sharareh , Chen Wei , Lee Chen-Ting , Zhou Yingchun , Owzar Kouros , Chi Jen-Tsan , Horton Janet K. 
Published: August 2015

Abstract
Background: Breast radiotherapy is currently “one size fits all” regardless of breast cancer subtype (eg. luminal, basal). Emerging clinical data suggests that these distinct subtypes of breast cancer have unique patterns of response to radiation. There is a clinical need to identify radiation response biomarkers in order to provide individualized and optimal radiotherapy. Here we report on gene expression profiles associated with radiation response from: i) a rare clinico-genomic data in women treated with preoperative breast radiation and, ii) data from a pilot study of 16 biologically diverse breast tumor cell lines. Methods: Microarray analysis was done using the Affymetrix GeneChip® Human Transcriptome Array 2.0 (HTA 2.0) and the Affymetrix HU133A2.0 arrays. RNA was harvested from paired pre- and post-radiation formalin-fixed paraffin-embedded breast cancer tissue in 26 patients treated with radiation prior to surgical resection. In addition, RNA was obtained from 16 biologically diverse breast cancer cell lines exposed to radiation treatment (5Gy and 0Gy). The genes with the highest coefficient of variation were selected and a paired sample t-test was used to evaluate the significance of these changes. We compared the top 100 significantly induced human genes with genes identified as differentially expressed in the 16 breast cancer cell lines. Findings of interest were validated using qPCR, IHC and wWestern blotting assays. Results: Fourteen genes had significant adjusted p-values for differential expression in the human data and were differentially expressed among the radiation responsive versus non-responsive cell lines. Differential expression of genes involved in: apoptosis, cell cycle and MAPK signaling pathways were observed in both the luminal human tumors and the largely luminal radiation responsive cell lines. Differential expression of FAS, a critical modulator of programmed cell death, was highly significant. Conclusion: The known function of FAS suggests a biologically plausible role in breast subtype specific radiation response. Induction of FAS is seen in human tissue, and preferentially in luminal breast cancer cell lines.
Citation Format: Sharareh Siamakpour-Reihani, Wei Chen, Chen-Ting Lee, Yingchun Zhou, Kouros Owzar, Jen-Tsan Chi, Janet K. Horton. Gene expression profiling after radiation in human breast cancer specimens and breast cancer cell lines. [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 3331. doi:10.1158/1538-7445.AM2015-3331
Abstract 3338: Pharmacological inhibition of MRK/ZAK kinase for the treatment of medulloblastoma
Authors: Ruggieri Rosamaria , Markowitz Daniel , Powell Caitlin , Tran Nhan , Vanan Magimairajanissai , He Mingzu , Al-Abed Yousef , Symons Marc 
Published: August 2015

Abstract
Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiation therapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain.
We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell cycle arrest after ionizing radiation. Here we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a small molecule inhibitor of MRK, M443, which binds to MRK in an irreversible fashion and inhibits its activity. We found that M443 strongly radio-sensitizes UW228 medulloblastoma cells as well as IMB226 patient-derived primary cells. M443 also inhibits radiation-induced activation of both p38 and Chk2, two proteins that act downstream of MRK and are involved in DNA damage-induced cell cycle arrest. We also tested the effect of M443 in an animal model of medulloblastoma that employs orthotopic implantation of IMB226 medulloblastoma cells in nude mice. Intra-tumoral delivery of M443 alone significantly extended animal survival by 5 days compared to vehicle treatment. Combination treatment of M443 with radiation at 2 × 3 Gy, that is not effective on its own (1 day of additional survival over control), achieved a synergistic increase in survival (15 days over the control survival time). Western blotting of tumor lysates demonstrated strong inhibition of MRK activity.
In conclusion, we have developed a new small molecule inhibitor of MRK/ZAK that radio-sensitizes medulloblastoma cells. We hypothesize that combining radio-therapy with M443 will allow us to lower the radiation dose while maintaining therapeutic efficacy, thereby minimizing radiation-induced side effects.
Citation Format: Rosamaria Ruggieri, Daniel Markowitz, Caitlin Powell, Nhan Tran, Magimairajanissai Vanan, Mingzu He, Yousef Al-Abed, Marc Symons. Pharmacological inhibition of MRK/ZAK kinase for the treatment of medulloblastoma. [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 3338. doi:10.1158/1538-7445.AM2015-3338
Abstract 3339: Silibinin improves radiotherapeutic efficacy in prostate cancer by reducing IR-induced toxicity and EMT
Authors: Nambiar Dhanya K. , Rajamani Paulraj , Jain Anil , Deep Gagan , Agarwal Rajesh , Singh Rana P. 
Published: August 2015

Abstract
Radiotherapy of prostate carcinoma is well established and frequently utilized in a significant proportion of cancer patients. However, two major concerns with radiotherapy is the effect on normal tissues and development of more invasive-radioresistant population. We have previously shown that the use of a plant flavonoid, silibinin can radiosensitize prostate cancer cells preferentially in vitro, by inhibiting DNA damage repair. We extended this study further, to validate the effects of silibinin in improving the radiotherapeutic efficacy in vivo. Our results showed that, in vivo, silibinin strongly radiosensitized DU145 tumor xenograft inhibition (84%, P&lt;0.01) with higher apoptotic response (10-fold, P&lt;0.01) and reduced repair of DNA damage as evidenced by reduced Chk2 activation and enhanced pH2A.X foci in tumor tissues. Interestingly, we also observed that silibinin could rescue the mice from IR-caused hematopoietic injury and normal tissue toxicity. Studies have shown that ionizing radiation (IR) increases the vascularity and invasiveness of surviving radioresistant cancer cells. This invasive phenotype of radioresistant cells is an upshot of radiation induced pro-survival and mitogenic signaling in cancer as well as endothelial cells. In the current study, we demonstrate that silibinin can also radiosensitize endothelial cells by inhibiting expression of pro-angiogenic factors. Combining silibinin with IR not only down-regulated endothelial cell proliferation, clonogenicity and tube formation ability rather it significantly reduced migratory and invasive properties of PCa cells which were otherwise marginally affected by IR treatment alone. We have found that most of the pro-angiogenic, migratory and EMT promoting proteins were up regulated in response to IR in PCa cells. All of these invasive and EMT promoting actions of IR were markedly decreased by silibinin. Further, we found that potentiated effect was an end result of attenuation of IR activated mitogenic and pro-survival signaling, including Akt, Erk1/2 and STAT-3 by silibinin. Therefore, the study not only underlines the preferential radiosensitizing ability of silibinin in PCa, but also shows its efficacy in modulating IR-induced toxicity in normal cells and EMT in PCa cells.
Citation Format: Dhanya K. Nambiar, Paulraj Rajamani, Anil Jain, Gagan Deep, Rajesh Agarwal, Rana P. Singh. Silibinin improves radiotherapeutic efficacy in prostate cancer by reducing IR-induced toxicity and EMT. [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 3339. doi:10.1158/1538-7445.AM2015-3339