bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3470: Obesity and metformin alter progression of triple negative breast cancer
Authors: Camacho Laura , Xue Lei , Dobrolecki Lacey , Hilsenbeck Susan G. , Nagi Chandandeep , Putluri Nagireddy , Lewis Michael T. , Sreekumar Arun , Jiralerspong Sao 
Published: July 2016

Abstract
Background: Epidemiological studies from us and others have reported an association of obesity with more aggressive breast tumors and &gt;30% higher risk of recurrence and mortality compared to normal weight patients. This includes poorer outcomes for triple negative breast cancer (TNBC), an aggressive subtype with early recurrence and shorter survival. Metformin is a leading frontline therapy for type 2 diabetes and its safety profile is well documented. Laboratory and clinical studies including ours suggest that metformin may have anti-tumor effects in breast cancer. However, the nature and molecular mechanisms of these correlations are poorly understood.
Experimental design and methods: We used a PDX (patient-derived xenograft) breast cancer model in diet-induced obese mice to study how obesity promotes breast cancer growth and how metformin antagonizes these effects. After feeding the mice with a high-fat diet (HFD) vs. a control diet (CD), we transplanted a TNBC PDX into the mammary fat pads. When tumors reached about 50 mm3, mice in HFD and CD groups were randomly assigned to metformin treatment or no treatment. Tumor volumes were measured bi-weekly, and blood, tumors, and organs were collected after 4 weeks of treatment. Histological and immunohistochemical staining, serum adipokines array and metabolomics and lipidomics analyses were performed to examine potential mechanisms.
Results: HFD (obese) group compared to CD (lean) group was associated with larger tumors, whereas metformin compared to no treatment was associated with smaller tumors. A panel of adipokines and metabolites was identified to be differentially expressed between the groups.
Conclusion: Our results suggest a growth promoting effect of obesity in TNBC, while metformin appears to have the opposite effect. The identification of adipokines and metabolites involved in these effects will help us understand the mechanisms by which obesity and metformin alter the progression of TNBC.
Citation Format: Laura Camacho, Lei Xue, Lacey Dobrolecki, Susan G. Hilsenbeck, Chandandeep Nagi, Nagireddy Putluri, Michael T. Lewis, Arun Sreekumar, Sao Jiralerspong. Obesity and metformin alter progression of triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3470.
Abstract 3484: Analysis of in situ expression of hormone receptors and proliferation marker at a single cell level in breast cancer tissues
Authors: Ueno Takayuki , Isaka Hirotsugu , Itoh Hiroki , Miyamoto Kaisuke , Kitamura Manami , Imoto Shigeru 
Published: July 2016

Abstract
Background: Hormone receptors and proliferation markers are critical parameters for treatment selection of breast cancer patients. The expression of different parameters are currently assessed separately in different tissue sections but it is unclear how different parameters are co-expressed in a single cell in breast cancer tissues.
Samples and Methods: Breast cancer tissues from fifty-one patients with ER-positive HER2-negative breast cancer were analyzed. Expressions of ER and PgR were assessed in association with Ki67 using dual fluorescence immunohistochemistry with specific antibodies: SP-1 (abcam, Tokyo), 1E2 (Roche Diagnostics GmBH, Germany), and MIB1 (Dako Japan, Tokyo), respectively. More than 500 cancer cells were assessed in each tissue. Expression levels of each marker in a single cell were semi-quantitatively assessed by MetaMorph image analyzer (Molecular Devices Japan, Tokyo). All statistical analyses were performed using JMP ver.8.01 (SAS Institute Japan, Tokyo).
Results: To validate the system, Ki67 LI in breast cancer tissues were compared between this system and the regular DAB system. The two systems showed a good concordance (p &lt; 0.0001). All cancer tissues expressed ER. There were two distinct populations among Ki67-positive proliferating cells according to PgR expression status: PgR-positive proliferating cells and PgR-negative proliferating cells. Since cell proliferation is regulated in cancer cells by at least two different drivers including hormone receptor and growth factor, it is conceivable that these two populations depend on different driving systems. Indeed, tissues with dominantly PgR-positive proliferating cells showed mostly histological grade 1 (15/20, 75%), while most of tissues with PgR-negative proliferating cells showed grade 2 and 3 (22/31, 71%) (p = 0.0025 by chi square test). Moreover, the multivariate analysis using the ordered logistic regression analysis showed that PgR status in proliferating cells is an independent factor associated with histological grade (p = 0.003) while PgR expression rate and Ki67 LI were not (p = 0.3 and 0.25, respectively).
Conclusion: PgR status in Ki67-positive proliferating cells is associated with histological grade in ER positive HER2-negative breast cancers. Our results suggest that different driving systems give different expression patterns of PgR and Ki67 at a single cell level, which may distinguish between luminal A and luminal B cancers.
Citation Format: Takayuki Ueno, Hirotsugu Isaka, Hiroki Itoh, Kaisuke Miyamoto, Manami Kitamura, Shigeru Imoto. Analysis of in situ expression of hormone receptors and proliferation marker at a single cell level in breast cancer tissues. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3484.
Abstract 3491: Rational combination of targeted agents and BH3 mimetics to improve cancer treatment
Authors: Montero Joan , Sadowicz Dorota E. , Ryan Jeremy , Yoon Charles H. , Haq Rizwan , Letai Anthony 
Published: July 2016

Abstract
Background: In the clinic is often observed that melanoma cancer patients first respond to targeted therapeutic agents like dabrafenib showing tumor burden shrinkage, but subsequently relapse with tumors that are more aggressive, no longer responsive to therapy and showing acquired metastatic capacity. Most chemotherapeutic agents kill via the mitochondrial pathway of apoptosis, but unfortunately tumors frequently are able to survive, often adapting their antiapoptotic strategy. We used a variant of the functional predictive test dynamic BH3 profiling (DBP) to determine the tumor's antiapoptotic defense adaptation over time, and rationally identify combination of therapies to restore programmed cell death.
Hypothesis: By using different BH3 peptides in DBP we can determine the adaptive tumor's antiapoptotic defense and adjust therapy to improve cancer cell death.
Results: In BRAF mutant melanoma, cKIT mutant GIST and HER2 overexpressing breast cancer cell lines, we performed DBP over time using different BH3 peptides: BIM, BAD, PUMA, MS1 and NOXA. We observed that when they are treated with specific targeted agents against their oncogenic drivers, there is an increase in MCL-1 dependence over time. This observation points to a possible tumor defense mechanism conferring resistance against anticancer drugs. Based on these observations, we exploited these altered dependencies by pretreating the cancer cells with these targeted agents and combining them with novel BH3 mimetics targeting MCL-1 to synergistically enhance cell death.
Exploiting DBP's capacity to measure changes in priming without the requirement for prolonged ex vivo culture, we assessed if this antiapoptotic evolution was also present in primary melanoma samples. Using FACS-based DBP to select for specific tumor populations, we tested the possible use of BH3 mimetics in combination with targeted agents to improve cancer treatment in the clinic.
Conclusions: Our preliminary results reveal the use of dynamic BH3 profiling to be used not only as a powerful real-time tool to predict chemotherapy response but also to evaluate the rational combination of targeted agents with BH3 mimetics in vitro and in the clinic.
[R.H. and A.L. contributed equally to this work.]
Citation Format: Joan Montero, Dorota E. Sadowicz, Jeremy Ryan, Charles H. Yoon, Rizwan Haq, Anthony Letai. Rational combination of targeted agents and BH3 mimetics to improve cancer treatment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3491.
Abstract 3496: TRAF2 protects mammary epithelial and cancer cells from endoplasmic reticulum stress-induced apoptosis
Authors: Habelhah Hasem , Zhang Laiqun , Xialikaer Ainiwaer , Blackwell Ken 
Published: July 2016

Abstract
TRAF2 plays a key role in the immune response and cell survival by regulating the NF-κB and JNK pathways in response to most members of the TNF superfamily. TRAF2 has also been shown in cell culture systems to mediate IRE1α-induced activation of the ASK1-JNK pathway to promote apoptosis under conditions of acute endoplasmic reticulum (ER) stress. Gene knockout studies revealed that mice deficient for RANKL or NF-κB display defects in osteoclastogenesis and lactating mammary-gland development. Here, we report that TNFα and TRAF2 double knockout (DKO) mice develop with normal bone morphology and density, but the female mice display a severe lactation defect due to significantly increased apoptosis of cells in the lobuloalveolar tree. Unexpectedly, RANKL-induced activation of the canonical NF-κB pathway is not only normal in DKO mammary epithelial cells (MECs), but the expression of the NF-κB target genes is significantly enhanced due to constitutive activation of the non-canonical NF-κB pathway in the absence of TRAF2. On the other hand, cytotoxicity assays revealed that DKO MECs exhibit significantly increased susceptibility to apoptosis induced by chronic ER stress, but not by death receptor or DNA damage. In addition, siRNA-mediated knockdown of TRAF2 in breast cancer cells significantly sensitized the cells to chronic ER stress-induced apoptosis in a RIP1-dependent manner. These data suggest that the physiological function of TRAF2 is to protect the cells from apoptosis under conditions of pathologically relevant chronic ER stress. Given that the lactating MECs and rapidly growing cancer cells have high demands for protein syntheses and ER stress responses, our findings suggest that inhibition of the IRE1α-TRAF2 pathway could be used as a novel adjuvant therapy to treat rapidly proliferating cancer cells.
Citation Format: Hasem Habelhah, Laiqun Zhang, Ainiwaer Xialikaer, Ken Blackwell. TRAF2 protects mammary epithelial and cancer cells from endoplasmic reticulum stress-induced apoptosis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3496.
Abstract 350: Visualizing alectinib distribution in mice brain by using MALDI mass spectrometry imaging technique
Authors: Aikawa Hiroaki , Hayashi Mitsuhiro , Ryu Shoraku , Yamashita Makiko , Ohtsuka Naoto , Nishidate Masanobu , Hamada Akinobu 
Published: July 2016

Abstract
[Introduction]
In the development of anticancer drug, measurement of drug concentration in target tissue has been thought to be crucial for predicting its efficacy and safety. However, measuring homogenized tissue by using quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) completely loss the spatial information of the compound in a target tissue. Mass spectrometry imaging (MSI) has been recently applied as innovative tools to detect pharmaceutical distributions in heterogeneous targets; however, it still needs to be improved in quantitative capability or reproducibility.
[Purpose]
We propose quantitative approach for MSI (qMSI) that administere matrix-assisted laser desorption ionization (MALDI)-MSI, concurrently with LC-MS/MS by using serial sections. We applied qMSI for visualizing spatial distribution of alectinib, novel ALK inhibitor, in mouse brain and examined the effect of MDR1 (p-glycoprotein) on the pharmacokinetic profiles in FVB and Mdr1a/b knockout mice.
[Method]
Pharmacokinetic study of alectinib was conducted in FVB and Mdr1a/b KO mice. Plasma, cerebrospinal fluid (CSF) and brain tissue were collected at 1, 1.5, 2, and 4 hours after a single oral administration dose of 4 and 20 mg/kg. The concentration of alectinib in plasma, CSF and brain tissue sections was measured by LC-MS/MS. The distribution of alectinib in mice brain tissue section was visualized by qMSI that we established.
[Results]
Developing qMSI showed the brain distribution of alectinib in the range from 1.2 to 952.6 pg/mm2 per each section, and the results made with qMSI were in excellent agreement with the complementary measurements by using laser-micro dissection to verify the exposure level. While plasma alectinib concentrations had no difference between both mice, the diffuse alectinib distributions in brain were observed in Mdr1a/b knockout compared with that in FVB mice. The dominant localization of alectinib in choroid plexus and brain blood vessels of FVB mice was observed by 20 μm resolution MSI analysis.
[Conclusion]
Our qMSI technique is expected to contribute to the development of anticancer drugs and translational research by visualizing drug distribution in target organs and tumors.
Citation Format: Hiroaki Aikawa, Mitsuhiro Hayashi, Shoraku Ryu, Makiko Yamashita, Naoto Ohtsuka, Masanobu Nishidate, Akinobu Hamada. Visualizing alectinib distribution in mice brain by using MALDI mass spectrometry imaging technique. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 350.
Abstract 3500: Mitochondrially targeted p53 domains as a stand alone or adjunct to paclitaxel for the treatment of ovarian cancer
Authors: Lu Phong , Lim Carol S. 
Published: July 2016

Abstract
Although the main function of p53 is a nuclear transcription factor that has important roles in cell cycle arrest, DNA repair, and apoptosis, p53 can directly trigger the intrinsic apoptotic pathway through the mitochondria. p53 has been known to bind to mitochondrial anti-apoptotic proteins (Mcl-1, Bcl-2 and Bcl-XL) and pro-apoptotic proteins (Bak and Bax), which will cause the oligomerization of Bak and Bax. The result is the formation of permeable pores on the mitochondrial outer membrane, which in turn cause the release of cytochrome c and activation of caspase-3. Targeting p53 to the mitochondria is an attractive approach because it can cause a rapid apoptotic response. We have introduced the mitochondrial targeting signal (MTS) from Bak or Bax to the C-terminus of p53 and have shown the superior efficacy of p53-BakMTS and p53-BaxMTS over wtp53 in many human cancer cell lines. We have identified that the DNA binding domain (DBD) of p53 may be the minimal domain of p53 required for apoptosis. Our preliminary data in SKOV-3 ovarian cancer cells also suggests that DBD-BakMTS may work just as well as full length p53-BakMTS. In addition to BakMTS and BaxMTS, attaching pro-apoptotic factors such as Noxa or Bid to p53 has created a chimeric gene construct that show superior cell death activity than wide type p53. Our goal is to use a novel version of p53 directed to the mitochondria as a direct apoptogen to treat ovarian cancer, the most lethal gynecological malignancy with 69% of patients succumbing to this disease. Our next step will be to test these constructs in vivo using the syngeneic ID8 mouse model. To determine the activity of these mitochondrially targeted p53 constructs, TMRE, 7-AAD, and caspase 3/7 assays were performed in many human ovarian cancer cell lines including SKOV-3, OVCAR-3, Kuramochi, and mouse ovarian ID8 cells that have been transfected with our constructs. In all of our cell death and apoptotic assays, p53-Bax-MTS, p53-BakMTS, and p53-Noxa are always superior to wide type p53, regardless of the p53 status of the cells. Furthermore, we have also tested the possibility of combining our p53 constructs with paclitaxel, the current standard of care for ovarian cancer. Our p53 constructs showed a synergistic effect with paclitaxel and was able to reduce its IC5, indicating the possibility of dose-lowering of this highly toxic drug. Our ultimate goal is to use mitochondrially targeted p53 constructs that directly induce apoptosis alone or in combination with other chemotherapy drugs for the treatment of ovarian cancer.
Acknowledgements: NIH CA151847
Citation Format: Phong Lu, Carol S. Lim. Mitochondrially targeted p53 domains as a stand alone or adjunct to paclitaxel for the treatment of ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3500.
Abstract 3513: Promoting TRAIL apoptosis signaling using 17-beta-hydroxywithanolides
Authors: Brooks Alan D. , Xu Ya-ming , Wijeratne E. M. Kithsiri , Tewary Poonam , Henrich Curtis J. , Thomas Cheryl L. , Gunatilaka A. A. Leslie , Sayers Thomas J. 
Published: July 2016

Abstract
We have previously reported that withanolide E (WE), a steroidal lactone from Physalis peruviana, was highly active in sensitizing various human carcinoma cell lines to TRAIL-mediated apoptosis. Treatment of cancer cells with WE induced a reduction in the levels of the antiapoptotic proteins cFLIPL and cFLIPS, resulting in an increased activation of caspase-8 on subsequent TRAIL binding to its death receptors DR4 or DR5. The reduction in cFLIPL and cFLIPS was due to their destabilization and increased degradation by the proteasome. Interestingly, WE (a 17-beta-hydoxywithanolide, 17-BHW) was a far superior TRAIL sensitizer than more widely studied withaferin A (WFA) and its analogues, which lack the 17-beta-hydroxy group and bear an opposite side chain orientation, exhibit more promiscuous reactivity and are much more directly toxic to cells. Therefore, over 30 natural and semi-synthetic 17-BHWs were evaluated for their ability to promote death ligand-mediated cancer cell death. The 17-BHWs used in this work were obtained by the application of an efficient method of plant biomass production involving our innovative and patented soil-less aeroponic cultivation of P. crassifolia and P. peruviana and by chemical modification of natural withanolides produced by these plants. Our studies identified several 17-BHWs that were 4-8 fold more potent than WE in sensitizing the renal carcinoma cells ACHN to TRAIL-mediated apoptosis. These more active 17-BHWs were also more efficient at reducing cellular levels of cFLIPL and cFLIPS and enhancing caspase-8 activation. Preliminary structure activity relationship (SAR) studies suggested that the enone moiety in ring A was essential for activity. In addition acetoxylation at C-18, an alpha orientation of the lactone group and the double bond at C-24(25) of the lactone ring played important roles in determining the activity of 17-BHWs as TRAIL sensitizers. This suggests that the 17-BHW scaffold is amenable to optimization by a medicinal chemistry approach, which could lead to the identification of highly active natural product-based sensitizers of cancer cells to TRAIL-mediated apoptosis. The cellular molecular target(s) of active 17-BHWs are currently under further investigation.
Funded by FNLCR Contract HHSN261200800001E
Citation Format: Alan D. Brooks, Ya-ming Xu, E. M. Kithsiri Wijeratne, Poonam Tewary, Curtis J. Henrich, Cheryl L. Thomas, A. A. Leslie Gunatilaka, Thomas J. Sayers. Promoting TRAIL apoptosis signaling using 17-beta-hydroxywithanolides. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3513.
Abstract 3515: MiR-320b-regulated TRIAP1 prevents mitochondria fragmentation and apoptosis by controlling cytochrome c release in nasopharyngeal carcinoma
Authors: Li Ying-Qin , Liu Na , Ma Jun 
Published: July 2016

Abstract
Mitochondria play critical roles in apoptosis. Imbalance of mitochondria fusion/fission leads to mitochondrial fragmentation and initiates intrinsic apoptosis, but the regulation of mitochondrial fragmentation in nasopharyngeal carcinoma (NPC) remains undefined. Here we show that TRIAP1 is aberrantly overexpressed and associated with poor survival in NPC patients. TRIAP1 overexpression promotes cell growth and suppresses NPC cell death in vitro and in vivo, whereas TRIAP1 knockdown inhibits cell tumorigenesis and enhances apoptosis through induction of mitochondrial fragmentation, membrane potential alteration and release of cytochrome c from mitochondria to cytosol. In intersection with our previous miRNA data and available bioinformatics algorithms, we identified miR-320b as a negative regulator of TRIAP1 expression. Further studies show that miR-320b suppresses NPC cell proliferation and enhances mitochondrial fragmentation and apoptosis by targeting TRIAP1. Moreover, loss of miRA-320b expression is conversely correlated with TRIAP1 overexpression and poor prognosis in NPC patients. This study reveals the regulation of miR-320b/TRIAP1 in mitochondrial fragmentation and apoptosis, and suggests potential therapeutic targets for NPC treatment.
Citation Format: Ying-Qin Li, Na Liu, Jun Ma. MiR-320b-regulated TRIAP1 prevents mitochondria fragmentation and apoptosis by controlling cytochrome c release in nasopharyngeal carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3515.