Highlights of This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Tags: Highlights Source Type: research

Abstract B34: Inhibition of breast cancer cell metastasis with a non-cyclooxygenase inhibitory derivative of sulindac by suppressing TGFbeta/miR-21 signaling
This study is supported by the NIH/NCI R01 Grant (1R01CA192395) and the American Cancer Society Research Scholar Grant (RSG-13-265-01-RMC).Citation Format: Bin Yi, Hong Chang, Xiangling Feng, Ruixia Ma, Gary A Piazza, Yaguang Xi. Inhibition of breast cancer cell metastasis with a non-cyclooxygenase inhibitory derivative of sulindac by suppressing TGFbeta/miR-21 signaling. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B34. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Yi, B., Chang, H., Feng, X., Ma, R., Piazza, G. A., Xi, Y. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A34: Estrogen induces RAD51C expression and localization to sites of DNA damage
Homologous recombination (HR) is a conserved process that maintains genome stability and cell survival by repairing DNA double-strand breaks (DSBs). The RAD51-related family of proteins is involved in repair of DSBs, consequently, deregulation of RAD51 causes chromosomal rearrangements and stimulates tumorigenesis. RAD51C has been identified as a potential tumor suppressor and a breast and ovarian cancer susceptibility gene. Recent studies implicated estrogen as a DNA-damaging agent that causes DSBs. We found that in estrogen receptor (ER)α-positive breast cancer cells, estrogen transcriptionally regulates RAD51C exp...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Holz, M. K. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B33: The membrane associated cyclin D1 promotes contact-independent growth via phosphorylation of Akt1 Ser 473
The serine threonine kinase Akt plays a pivotal role in the control of cellular metabolism, survival, growth and cellular migration. Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates pRb, to promote cell cycle progression and functions as a nuclear collaborative oncogene. Herein, genetic deletion of cyclin D1 reduced and overexpression induced Akt1 activity in tissue culture and in vivo. Endogenous cyclin D1 augmented both the rate of onset and maximal cellular Akt1 activity. The cytoplasmic membrane-associated pool of cyclin D1, augmented Akt1 kinase activity, to thereby induce c...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Jiao, X., Chen, K., Xu, S., Ju, X., Ertel, A., Tian, L., Yu, Z., Sante, G. D., Wang, M., Li, Z., Pestell, T., Casimiro, M., Shen, D., Achilefu, S., Pestell, R. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A33: Biomarkers of Cdk5 driven neuroendocrine tumors
Conclusion: Four novel phosphoproteins downstream of Cdk5 comprise a set of biomarkers for Cdk5-dependent human NE tumors. The combination of these biomarkers with pathway specific therapies currently under development will constitute a coupled diagnostic-therapeutic regimen for personalized treatment of NE cancer patients.Citation Format: Angela M. Carter, Rahul Telange, Sarah Oltmann, Fiemu Nwariaku, Bruce Robinson, Elizabeth Grubbs, James Bibb. Biomarkers of Cdk5 driven neuroendocrine tumors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Carter, A. M., Telange, R., Oltmann, S., Nwariaku, F., Robinson, B., Grubbs, E., Bibb, J. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B32: Oncogenic role of snoRD93 in breast cancer cells
In this study, we compared the transcriptome profiles of human breast cancer cell lines, MCF-7 and MDA-MB-231, by using the next generation sequencing (NGS). MCF-7 cells were derived from the primary breast tumor, while MDA-MB-231 cells are highly metastatic. Our sequencing results showed that 13 snoRNAs was significantly overexpressed in MDA-MB-231 cells versus MCF-7 cells. In particular, we are interested in snoRD93, given its expression showing 27-time higher in MDA-MB-231 cells than MCF-7 cells. We further studied the oncogenic role of snoRD93 in MDA-MB-231 cells by using loss-of-function strategy. By employing cell vi...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Ma, R., Zhao, H., Patterson, D., Borchert, G., Xi, Y. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B31: Sulindac inhibition of tumor cell transformation
This study is supported by the NIH/NCI R01 Grant (1R01CA192395) and the American Cancer Society Research Scholar Grant (RSG-13-265-01-RMC).Citation Format: Zhipin Liang, Xiangling Feng, Hong Chang, Bin Yi, Ruixia Ma, Yaguang Xi. Sulindac inhibition of tumor cell transformation. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B31. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Liang, Z., Feng, X., Chang, H., Yi, B., Ma, R., Xi, Y. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A31: Reprimo, a potential tumor suppressor gene TP53-dependent, modulates negatively cell migration and invasion in the MDA-MB-231 breast cancer cell line
Background: Reprimo, a highly glycosylated protein, is a new downstream effector of p53-induced cell cycle arrest at the G2/M checkpoint, and a putative tumor suppressor gene frequently silenced via methylation of its promoter region in several malignances. The aim of this study was to characterize the epigenetic inactivation and its biological function in BC cell lines.Methods: The correlation between Reprimo methylation and loss of mRNA expression was assessed in six breast cancer cell lines by methylation specific PCR (MSP), 5-Aza-2'-deoxycytidine treatment and qRT-PCR assays. MDA-MB-231 cells were chosen to investigate...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Buchegger, K., Viscarra, T., Ili, C. G., Riquelme, I., Letelier, P., Corvalan, A., Brebi, P., Huang, T. H.-M., Roa, J. C. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B30: Resistance to Photodynamic Therapy in Non-Melanoma Skin Cancer Cells
Introduction: Squamous skin cancer is one of the most common neoplasia worldwide and may be preceded by Bowen's disease (BD) and Actinic Keratosis (AK). These preneoplastic lesions can be treated with photodynamic therapy (PDT). PDT causes cell death mainly by reactive oxygen species (ROS) produced through a combination of O2, a photosensitizer and light. BD and AK have well overcomes after PDT. However, high recurrence rates of some lesions have been reported.Objective: To generate resistant cells to PDT as an in vitro model for future studies.Methodology: HSC-1 cells from human squamous cell cancer (SCC) of skin were use...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Leon, D., Silva, R., Inada, N., Kurachi, C., Ili, C. G., Brebi, P., Roa, J. C. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A30: The effects of Berberis vulgaris on bacterial inhibition and the p53 gene in cancerous Caenorhabditis elegans
This study aims at finding the most effective natural antibacterial remedy. The disk diffusion method was used to compare the antibacterial properties of manuka honey, barberry, aloe vera, and colloidal silver. After a 48-hour incubation period, the zone of inhibition was measured for the following bacteria: Bacillus megaterium, Serratia marcescens, Pseudomonas fluorescens, Rhodospirillum rubrum, and Escherichia coli. Barberry was the most efficient natural product (p=0.02). Further tests were performed to determine whether barberry contained strong anticancer properties. Barberry was tested on Caenorhabditis elegans (C.el...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Bhatt, J. P. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B29: ZNF516 a potential tumor suppressor gene candidate is implied in tumor progression in cervical cancer
Background: In Cervical Cancer (CC) the role of HPV is fundamental; however, not all HPV infected women will develop this disease. Therefore, other mechanisms, such as silencing of tumor suppressor genes (TSG), could be implied in cervical carcinogenesis. In a previous study, we constructed methylation microarrays, where we found promoter aberrant hypermethylation of ZNF516 gen in CC, postulating it as TSG candidate. The aim of this study was to characterizer ZNF516 role in cervical carcinogenesis and cell cycle.Materials and methods: ECT1 E6/E7 (immortalized normal squamous epithelia cell line) and three CC cell lines: Si...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Ili, C. G., Viscarra, T., Araya, J. C., Lopez, J., Mora, B., Retamal, J., Bellolio, E., Aedo, S., Roa, J. C., Brebi, P. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B28: FKBP6 gene is involved in progression of cervical cancer
Introduction: Cervical Cancer (CC) is an important heath problem in developing countries. The silencing of tumor suppressor genes (TSG) could be implied in cervical carcinogenesis. Methylation microarray showed an aberrant hypermethylation of FKBP6, a potential TSG gen in CC. The aim of this study was to characterizer FKBP6 role in cervical carcinogenesis.Materials and methods: ECT1 E6/E7 (immortalized normal squamous epithelia cell line) and three CC cell lines: SiHa, C-4I and C-33A were cultivated for experiments. FKBP6 expression was determined by qRT-PCR and western blot. Treatment with 10 μM 5-aza-2'deoxycytidine (...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Ili, C. G., Viscarra, T., Araya, J. C., Lopez, J., Mora, B., Retamal, J., Aedo, S., Bellolio, E., Roa, J. C., Brebi, P. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A28: Mechanistic study involving the combined antiproliferative effect of Etoricoxib- cyclooxygenase-2 inhibitor and cholecystokinin-2 receptor antagonist in human pancreatic cancer cells
Conclusion: The combined effect of Cyclooxygenase-2 inhibitor and Cholecystokinin-2 Receptor antagonists was calculated using Chaou Tatlay method. A combination index was calculated. As a class NSAIDs possess analgesic, antipyretic, anti-inflammatory, and there is persuasive evidence that COX-2 inhibitor suppress cancer cell proliferation owing to their role in apoptosis, compelling evidence suggest that COX-2 over-expression promotes whereas COX-2 inhibition prevents tumor initiation and promotions. NSAIDs and COX-2 selective inhibitors may have different effects on cancer may be stage dependent therefore a better underst...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Sikka, M. Tags: Managing G2/M Control: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA27: Perturbation of host cellular regulatory networks by human papillomaviruses
Human papillomaviruses (HPVs) are small viruses with ~8,000 bp double-stranded, circular genomes. There are over 200 HPV types and they all infect epithelial cells. While most HPV infections are subclinical others cause overt lesions. Most HPV-associated lesions are benign but some "high-risk" HPVs cause lesions that have a propensity for malignant progression and approximately 10% of all human cancers worldwide are caused by high-risk HPV infections. HPV-associated cancers generally represent non-productive infections, i.e. viral proteins are synthesized but no infectious virus is produced. HPV-associated cancer...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Münger, K. Tags: Derailed by Infection: Viral-mediated Cell Cycle Dysfunction: Oral Presentations - Invited Abstracts Source Type: research

Abstract B27: Kinetochore-microtubule attachments as a precision therapy target
Glioblastoma multiforme (GBM) is an aggressive and refractory cancer with limited therapeutic strategies and poor survival. One challenge in treating this disease is the ability of single glioblastoma stem-like cells (GSCs) to initiate tumors. To expand the therapeutic repertoire for GBM we performed RNAi screening in GSCs and a proposed cell of origin, neural crest stem cells (NSCs). In these screens we identified multiple regulators of kinetochore-microtubule attachments as specifically required for GSC survival. Kinetochores are composed of hundreds of proteins that form dynamic attachments between microtubules and chro...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Herman, J. A., Paddison, P. J., DeLuca, J., Olson, J. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A27: Cell cycle control and drugs targeting the bioenergetics of cancer
Differences in responsiveness to chemotherapeutics among patients may be associated with multiple cell types that can be found in tumors and the circulation. Recurrent or refractory disease may result from natural selection of cells in response to therapy. To design new drugs and make better use of existing drugs differences between diseased and disease causing cells in response to a specific drug requires investigation. The Warburg Effect is characteristic of the majority of cancer cell types both in tumors and the circulation. Drugs that target the underlying biochemistry of essential bioenergetic processes unique to can...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Shorr, R. Tags: Managing G2/M Control: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B26: MiR-200 is involved in anti-invasive activity of sulindac in colon cancer
This study is supported by the NIH/NCI R01 Grant (1R01CA192395) and the American Cancer Society Research Scholar Grant (RSG-13-265-01-RMC).Citation Format: Hong Chang, Xiangling Feng, Ruixia Ma, Yaguang Xi. MiR-200 is involved in anti-invasive activity of sulindac in colon cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B26. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Chang, H., Feng, X., Ma, R., Xi, Y. Tags: Other Topics: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B24: Ataxia-telangiectasia and Rad3-related (ATR) phosphorylation as a pharmacodynamic biomarker of ATR activation in solid tumor tissue models
Inhibitors of checkpoint kinases, such as ATR, Chk1 or Wee1, in combination with cytotoxic agents could enhance therapeutic efficacy compared to monotherapy, and these combination approaches are currently being extensively explored. The presence of replicative stress or deregulated S-phase in cancer has been recognized as a rationale for the use of ATR and Chk1 inhibitors with chemotherapy and efforts are underway to define genetic determinants that sensitize cancer cells to ATR inhibition. Pharmacodynamic (PD) biomarkers of drug activity are valuable tools in clinical trials using targeted agents to determine whether each...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Wilsker, D., Marrero, A. M., Dull, A., Pfister, T. D., Lawrence, S. M., Carter, J., Gottholm-Ahalt, M., Hollingshead, M., Doroshow, J., Parchment, R. E., Kinders, R. J. Tags: Replication Stress and DNA Damage Response: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B23: The deubiquitinating enzyme USP37 stabilizes Chk1 to promote the cellular response to replication stress
Ubiquitin-mediated proteolysis is a key regulatory process in cell cycle progression. Recently, we identified mutual antagonism between the deubiquitinase USP37 as and the tumor suppressor APCCdh1 to regulate S-phase entry. Here we report that elevated USP37 expression correlates with cellular transformation. Depletion of USP37 leads to diminished cellular proliferation and loss of viability in tumor cells. USP37-depleted cells exhibit altered replication kinetics and increased levels of the DNA damage markers H2AX and 53BP1 as well as increased sensitivity to agents that induce replication stress. Underlying the increased...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Singh, M., Pal, D., Burrows, A. C., Messina, A., Dickson, A., Summers, M. K. Tags: Replication Stress and DNA Damage Response: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B22: IT-141, a stabilized polymer micelle formulation, prolongs the pharmacodynamic effect of SN-38
IT-141 is a formulation of SN-38 encapsulated in an iron-stabilized polymer micelle. SN-38 is the active metabolite of irinotecan (CPT-11) which in combination with 5-FU and leucovorin is first-line FDA approved therapy for metastatic colorectal cancer. Although SN-38 is 1,000 times more potent than irinotecan alone, there is about 100-fold lower concentration of SN-38 in plasma from irinotecan. In the clinic only 2% to 10% of the administered dose of irinotecan is converted by carboxylesterases to SN-38 and there is great interpatient variability with toxicity. In vitro, IT-141 demonstrated nanomolar IC50s against a panel...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Sethuraman, J., Costich, T. L., Carie, A., Buley, T., Ellis, T., Semple, J. E., Vojkovsky, T., Sill, K., Bakewell, S. Tags: Replication Stress and DNA Damage Response: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A22: Preclinical evaluation of Bmi1 inhibition in pancreatic ductal adenocarcinoma
Pancreatic Ductal Adenocarcinoma (PDA) is the fourth leading cause of cancer-related deaths in the United States with a five-year survival rate of 6% and a rising mortality rate. The majority of patients present with advanced disease that is unresponsive to chemotherapy, highlighting the need for novel therapeutic strategies. Bmi1, a member of the Polycomb Group (PcG) family of transcriptional repressors, is known to be upregulated in PDA beginning in early pre-malignancy. Elevated Bmi1 expression in pancreatic tumors has been shown to correlate with poor prognosis, increased metastasis, and chemotherapy resistance in pati...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Eberle, J. A., Yuan, H., Palermo, C., Sastra, S. A., Cao, L., Moon, Y.-c., Dumble, M., Davis, T., Olive, K. P. Tags: Managing G2/M Control: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA21: Mitogenic signaling and the RB/p53 network
Cells entering the division cycle from a quiescent state (G0) in response to mitogenic cues synthesize one or more D-type cyclins (D1, D2, D3) that assemble in G1 phase with cyclin-dependent kinases CDK4 and/or CDK6. Notably, the transcription, assembly with CDK 4/6, and stability of D-type cyclins are each mitogen-dependent steps. Accumulation of cyclin D-dependent kinases in G1 phase leads to the progressive phosphorylation of the retinoblastoma protein (RB), facilitating transcription of E2F-responsive genes, including cyclins E and A, whose CDK2-dependent functions are normally required in S phase. Moreover, the stoich...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Sherr, C. J. Tags: Keynote Address: Oral Presentations - Invited Abstracts Source Type: research

Abstract A21: Epigenetic regulation of cell cycle progression at the G2/M transition and mitosis in high-risk leukemia
In conclusion, our results reveal that: 1) Ikaros functions as a tumor suppressor by repressing transcription of genes that are critical for G/M transition (CDC2) and mitotic progression (ANAPC1 and ANAPC7); 2) Ikaros represses transcription by inducing two distinct epigenetic alterations at promoters of its target genes and 3) CK2 inhibition with CX-4945 restores Ikaros function as a transcriptional regulator of CDC2, ANAPC1 and ANAPC7 in high-risk leukemia. These results provide novel insights into the control of cell cycle progression in high-risk leukemia and the mechanisms by which CK2 inhibitors exert their therapeut...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Song, C., Gowda, C., Ding, Y., Payne, K. J., Dovat, S. Tags: Managing G2/M Control: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA20: Exploiting CDK2-driven replication stress to repurpose cancer chemotherapy
Cyclin-dependent kinase 2 (CDK2) coordinates diverse process, including cell cycle entry and progression, DNA replication, and DNA damage and replication stress responses. Cancers frequently contain mutations in genes that regulate CDK2, which is also activated by oncogenic signaling. Because cancers have abnormally high CDK2 activity, most therapeutic strategies seek to inhibit CDK2. Our studies of CDK2 function during replication stress suggest an alternate approach: to harness high CDK2 activity as a therapeutic modality to cause irreparable DNA damage. In order to study the functions of CDK2 inhibitory phosphorylation ...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Richards, H., Zhao, H., Hughes, B. T., Clurman, B. E. Tags: Replication Stress and DNA Damage Response: Oral Presentations - Invited Abstracts Source Type: research

Abstract A20: Excess centrosomes induce p53-dependent senescence in endothelial cells
Excess centrosomes (>2 centrosomes/cell), which are prevalent in both tumor cells and tumor endothelial cells, lead to aneuploidy and chromosome instability. Therefore, understanding how excess centrosomes affect cell behaviors is critical for studying tumor progression and tumor angiogenesis. As demonstrated by previous literature, cells with excess centrosomes routinely undergo bipolar cell division to produce viable progeny. However, we found that endothelial cells were not able to maintain the percentage of cells with excess centrosomes, suggesting that excess centrosomes had a negative impact on endothelial cell cy...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Yu, Z., Kushner, E., Bautch, V. Tags: Getting out of Cycle: G0 and Senescence: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA19: Mechanisms of alternative telomere recombination
Telomere length maintenance is a requisite feature of cellular immortalization and a hallmark of human cancer. While most human cancers express telomerase activity, approximately 10-15% employ a recombination-dependent telomere maintenance pathway known as Alternative Lengthening of Telomeres (ALT), an incompletely understood process that is characterized by multi-telomere clusters. We have recently shown that a DNA double-strand break (DSB) response at ALT telomeres triggers long-range movement and clustering between chromosome termini, resulting in homology-directed telomere synthesis (Cho et. al. Cell 2014). Damaged tel...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Greenberg, R. A. Tags: Replication Stress and DNA Damage Response: Oral Presentations - Invited Abstracts Source Type: research

Abstract B19: The oncogenic TBX2 activates the ATM-CHK2-p53 axis to confer cisplatin resistance in breast cancer and melanoma
A prominent mechanism through which tumors develop resistance to DNA damaging chemotherapeutic agents is by cancer cells preferentially arresting in S-phase, thereby acquiring the ability to repair drug-induced DNA damage and consequently evading apoptosis. Combining DNA damaging therapies with targeted approaches that disrupt the DNA damage repair process may therefore prove to be more effective against such tumors. The developmentally important transcription factor TBX2 has been suggested as a novel anti-cancer drug target, as it is overexpressed in several cancers and possesses strong anti-senescence and pro-proliferati...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Kimani, S., Wansbelen, S., Davis, E., Peres, J., Prince, S. Tags: Replication Stress and DNA Damage Response: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A18: G1 cell cycle arrest is required for invasive behavior
The ability for a cell to breach the surrounding basement membrane and adopt an invasive phenotype is a critical, but poorly understood step in the progression of cancer. Like many aspects of cancer cell behavior, the genetic programs that regulate invasive behavior are likely shared with normal cell biological processes, as invasion occurs during embryonic development and immune surveillance. Due to difficulties of studying this dynamic behavior in vivo, elucidating the genetic and epigenetic controls of cell invasive activity has been difficult. Our laboratory uses a unique in vivo model to examine cell invasion that com...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Kohrman, A. Q., Chandhok, M., Zhang, W., Matus, D. Q. Tags: Getting out of Cycle: G0 and Senescence: Poster Presentations - Proffered Abstracts Source Type: research

Abstract B17: Targeting MK2 to improve temozolomide efficacy in glioblastoma
Glioblastoma is the most prevalent and aggressive form of brain cancer. The heterogeneous nature and survival mechanisms that glioblastoma tumors develop impede chemotherapy efficacy of temozolomide (TMZ) and result in tumor relapse. The p38 MAPK and its downstream kinase MK2 have been well established in regulating signaling pathways influencing inflammation, cell division and differentiation, as well as cell motility in response to a wide range of extracellular stimuli. Recent studies have identified p38 MAPK-MK2 pathway as an effector kinase complex that is activated following DNA damage and results in cell cycle arrest...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Gurgis, F., Day, B., Stringer, B., Johns, T. G., Munoz, L. Tags: Replication Stress and DNA Damage Response: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A17: Cell cycle control through DREAM and MMB complexes
The loss of cell cycle control is the most recognized trait of cancer cells. The ability of cells to exit the cell cycle has recently been shown to be dependent upon a large multi-protein repressor complex called DREAM. This complex represses the expression of all cell cycle genes during reversible cell cycle exit. In cycling cells, DREAM is disassembled and some of DREAM associated proteins form a new complex to promote cell cycle gene expression. These proteins that can act together both as repressors and activators of cell cycle gene expression are called the MuvB core. The MuvB core interacts with B-Myb during S phase ...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Guiley, K., Rubin, S. M. Tags: Getting out of Cycle: G0 and Senescence: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA16: Breaking the balance between E2F activators and atypical repressors: Consequences to development and cancer
E2F transcriptional activators and repressors regulate cell cycle-dependent gene expression. Using a series of loss- and gain-of-function alleles to dial E2F transcriptional output we show that mouse development is relatively insensitive to alterations in E2F levels and composition. However, modest increases in E2F output resulted in spontaneous hepatocellular carcinoma (HCC) without additional organ involvement, whereas decreases protected against HCC. Cell type- and temporal-specific gene ablation strategies defined a cell-autonomous oncogenic role for E2F1/3B and a tumor suppressor role for E2F7/8 in hepatocytes. Geneti...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Leone, G. W. Tags: E2F Family Functions: Alterations and Consequences: Oral Presentations - Invited Abstracts Source Type: research

Abstract B16: The nuclear IGF-1R regulates DNA damage tolerance through tyrosine phosphorylation of PCNA in human embryonic stem cells
Conclusions: Our results demonstrate a novel role of nIGF-1R in regulating the DNA damage tolerance pathway through PCNA phosphorylation and ubiquitination, potentially maintaining genomic stability in in hESC and in normal fibroblasts. In contrast, nIGF-1R does not interact with PCNA in cancer cell lines.Citation Format: Ahmed Waraky, Yingbo Lin, Eiman Aleem, Olle Larsson. The nuclear IGF-1R regulates DNA damage tolerance through tyrosine phosphorylation of PCNA in human embryonic stem cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; ...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Waraky, A., Lin, Y., Aleem, E., Larsson, O. Tags: Replication Stress and DNA Damage Response: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA15: The consequences of pRb inactivation: insights from a proteomic analysis of Rb loss
The retinoblastoma tumor suppressor protein associates with chromatin and regulates gene expression. The transcriptional signatures associated with RB1/Rb mutation are thought to give a picture of the cellular changes that occur when pRB is lost. We used proteomic profiling to examine the changes caused by the ablation of Rb in mouse lung and colon tissues, and compared these with transcript profiles. While the transcription of classic E2F target genes increased similarly in Rbko lung and colon, effects on protein levels were context-dependent. Proteomic changes were identified that were similar between Rb-mutant tissues b...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Nicolay, B. N., Danielian, P. S., Kottakis, F., Lapek, J. D., Sanidas, I., Miles, W. O., Dehnad, M., Tschöp, K., Gierut, J. J., Manning, A. L., Morris, R., Haigis, K., Bardeesy, N., Lees, J. A., Haas, W., Dyson, N. J. Tags: E2F Family Functions: Alterations and Consequences: Oral Presentations - Invited Abstracts Source Type: research

Abstract B15: Synergistic functions of E2F7 and E2F8 are critical to suppress stress induced skin cancer
E2F transcription factors are important regulators of the cell cycle, and unrestrained activation of E2F-dependent transcription is considered to be an important driver of tumor formation and progression. Although highly expressed in normal skin and skin cancer, the role of the atypical E2Fs, E2F7 and E2F8, in keratinocyte homeostasis, regeneration and tumorigenesis is unknown. Surprisingly, keratinocyte-specific deletion of E2F7 and E2F8 in mice did not interfere with skin development and wound healing. However, the rate for successful isolation and establishment of E2f7/8-deficient primary keratinocyte cultures was much ...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Westendorp, B., Thurlings, I., Martinez-Lopez, L., Zijp, M., Kuiper, R., Tooten, P., Vos, H., Burgering, B., Bruin, A. d. Tags: E2F Family Functions: Alterations and Consequences: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A15: Sin3B: a non-classical tumor suppressor
Perturbations in cell cycle regulators elicit hyperproliferation and the inability of cells to exit the cell cycle, which are common occurrences in cancer. Recently, we have demonstrated that Sin3B, an essential component of the mammalian histone deacetylase repressor complex, is required for oncogene-induced senescence both in vitro and in vivo. Surprisingly, primary Sin3B-null cells are not readily transformed upon ectopic expression of oncogenic Ras. Thus, these observations indicate that loss of Sin3B uncouples the ability to undergo senescence from the sensitivity to transformation in primary cells. To better understa...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Bainor, A. J., Ueberheide, B., David, G. Tags: Getting out of Cycle: G0 and Senescence: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR14: Real-time in-vivo image-guided cell-cycle perturbation to increase tumor chemosensitivity
Tumor heterogeneity has been recognized as a major reason for anticancer drug resistance and therapy failure in solid cancers. Therefore, we simply categorized the tumor heterogeneity as cycling and quiescent cancer cells. A multi-color genetic reporter system has been previously-developed termed fluorescence ubiquitination cell cycle indicator (FUCCI) (Cell 2008; 132:487-98) whereby cycling cells fluorescence yellow/green and quiescent cells fluoresce red. We demonstrated the monitoring of real-time spatiotemporal cell cycle dynamics of cancer cells throughout a live tumor intravitally using a FUCCI system. According to c...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Yano, S., Tazawa, H., Kishimoto, H., Kagawa, S., Kadowaki, Y., Ishido, N., Okamoto, T., Urata, Y., Takehara, K., Hoffman, R. M., Fujiwara, T. Tags: Getting out of Cycle: G0 and Senescence: Oral Presentations - Proffered Abstracts Source Type: research

Abstract B14: Feedback regulation between atypical E2Fs and APC/CCdh1 coordinates cell cycle progression.
In conclusion, we uncovered a feedback loop between atypical E2Fs and APC/CCdh1, which ensures balanced expression of cell cycle genes and normal cell cycle progression.Citation Format: Michiel Boekhout, Ruixue Yuan, Annelotte P. Wondergem, Hendrika A. Segeren, Elsbeth A. van Liere, Nesibu Awol, Imke Jansen, Rob MF Wolthuis, Alain de Bruin, Bart Westendorp. Feedback regulation between atypical E2Fs and APC/CCdh1 coordinates cell cycle progression.. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia ...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Boekhout, M., Yuan, R., Wondergem, A. P., Segeren, H. A., Liere, E. A. v., Awol, N., Jansen, I., Wolthuis, R. M., Bruin, A. d., Westendorp, B. Tags: E2F Family Functions: Alterations and Consequences: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR13: Germ-line mutations in CDC20 result in familial cancers via deregulation of the cell cycle
Conclusions: Our preliminary data suggest that L151R and N331K may drive cancer through the insensitivity of Cdc20 to the SAC. To our knowledge this is the first description of CDC20 as a cancer predisposition gene. The rapid division of cancer cells demands that they maintain high APC activity and this may represent an Achilles heel that can be exploited therapeutically.This abstract is also being presented as Poster B25.Citation Format: Ester Castellsague, Jian Carrot-Zhang, Isabelle Gamache, Barbara Rivera, Mohamed Moustafa, David Barford, Jacek Majewski, Jose Teodoro, William David Foulkes. Germ-line mutations in CDC20...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Castellsague, E., Carrot-Zhang, J., Gamache, I., Rivera, B., Moustafa, M., Barford, D., Majewski, J., Teodoro, J., Foulkes, W. D. Tags: Other Topics: Oral Presentations - Proffered Abstracts Source Type: research

Abstract A13: A new mitochondrial pool of cyclin E, regulated by Drp1, is linked to cell-density-dependent cell proliferation
Cyclin E is indispensable for release from quiescence. However, the regulation and function of the crucial cell cycle regulator cyclin E (CycE) remains elusive. Unlike other cyclins, CycE can be uniquely controlled by mitochondrial energetics, the exact mechanism being unclear. Using mammalian cells (in vitro) and Drosophila (in vivo) model systems in parallel, we show that CycE can be directly regulated by mitochondria through its recruitment to the organelle. Active mitochondrial bioenergetics maintains a distinct mitochondrial pool of CycE (mtCycE) lacking a key phosphorylation required for its degradation. Loss of the ...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Parker, D., Mitra, K. Tags: Targeting CDK/cyclins: Hormone Dependent Cancers and Beyond: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA12: Targeting the cell cycle in pediatric solid tumors
My lab is interested in understanding how proliferation and differentiation are coordinated during development and how those processes become uncoupled in pediatric solid tumors. We are also interested in identifying tumor vulnerabilities that can be exploited therapeutically. We have developed a unique resource for studying the developmental origins of childhood solid tumors and this resource is shared freely with no obligation to collaborate through the Childhood Solid Tumor Network (www.stjude.org/cstn). We have also developed a rigorous and comprehensive preclinical phase I/II/III testing program (Langenau et al. Cance...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Dyer, M. Tags: Rb Bench to Bedside: Novel Functions and Clinical Implications: Oral Presentations - Invited Abstracts Source Type: research

Abstract A12: The CDK4/CDK6 inhibitor abemaciclib inhibits transcriptional targets which facilitate growth in ER+ breast cancer cells
Abemaciclib (LY2835219) is an ATP-competitive inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), which is currently undergoing clinical evaluation as a single-agent treatment and in combination with the anti-hormonal therapy (SERD) fulvestrant in estrogen receptor positive (ER+) breast cancer (BrCa). Breast cancer cell line (15 lines) sensitivity to treatment with abemaciclib was assessed using multiple approaches including EdU incorporation, phosphorylation of retinoblastoma protein at serine 807/811 (pRb_s807/811) and RNA transcriptional profiling. We identified molecular features including ER-positivity (ER+), and ...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: McNulty, A. M., Burke, T., Dempsey, J. A., Marchal, C. C., Schade, A. E., Szpurka, H. P., Dowless, M. S., Stephens, J., Stephens, J., Edmondson, D., Stayrook, K., Caldwell, W. C., Buchanan, S., Merzoug, F. F., Beckmann, R. P. Tags: Targeting CDK/cyclins: Hormone Dependent Cancers and Beyond: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR11: APC/CCdh1 maintains primordial follicles, germinal vesicle arrest and ensures balanced segregation of chromosomes by enabling removal of Shugoshin-2 from chromosomes arms
Germ cells in mammals, including humans, remain arrested at the primordial follicle stage from a few days to many years depending on the species. At each hormonal cycle, a few of these cells grow in size to become fully-grown oocytes but remain arrested in meiotic prophase. A resumption of meiosis is heralded by germinal vesicle breakdown (GVBD), a gradual rise in Cdk1 activity, condensation of bivalent chromosomes, and their eventual alignment on metaphase plates with maternal and paternal kinetochore pairs pulled in opposite directions (co-orientation). The first meiotic division is triggered by activation of a form of t...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Rattani, A., Mejia, R. B., Roberts, K., Roig, M. B., Godwin, J., Eguren, M., Ogushi, S., Okaz, E., Pendas, A., Marcos, M., Herbert, M., Nasmyth, K. Tags: Managing G2/M Control: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA11: Transient CDK4/6 inhibition protects hematopoietic progenitors from chemotherapy-induced exhaustion
Conventional cytotoxic chemotherapy is highly effective in certain cancers, but causes dose-limiting damage to normal proliferating cells, especially hematopoietic stem and progenitor cells (HSPCs). Serial exposure to cytotoxics causes a long-term hematopoietic compromise ("exhaustion"), which limits the use of chemotherapy and success of cancer therapy. I will discuss the use of small-molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) contemporaneously with DNA damaging stimuli such as cytotoxic chemotherapy to protect HSPC from chemotherapy-induced exhaustion. Specifically, CDK4/6 inhibitors will ...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Sharpless, N. E. Tags: Getting out of Cycle: G0 and Senescence: Oral Presentations - Invited Abstracts Source Type: research

Abstract B11: Re-wired E2F function in response to RB loss as a potential driver of castration-resistant prostate cancer
Prostate cancer (PCa) is the most frequently diagnosed non-cutaneous malignancy, and second leading cause of cancer death in males in the United States, causing over 30,000 deaths per year. A crucial component to the development and progression of PCa is the activity of the androgen receptor (AR). AR promotes proliferation and is required for PCa cell growth and survival. As such, targeting the AR-signaling axis through androgen deprivation therapy (ADT) is the first line of therapy for PCa. However, cells invariably become resistant to this therapy and men relapse with the incurable form of the disease, castration-resista...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Mandigo, A. C., McNair, C., Schiewer, M. J., Xu, K., Li, F., Myles, B., Knudsen, K. E. Tags: E2F Family Functions: Alterations and Consequences: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR10: Exploiting the G2-M cell cycle checkpoint dependency in small cell lung cancer (SCLC) using pharmacological inhibitors of CHK1 and WEE1
In this study we investigated the effect of CHK1 (LY2606368) and WEE1 (AZD1775) inhibitors as therapeutic targets for SCLC.Methods: Protein and gene expression was determined by immunoblot and real-time-RT-PCR respectively. Effect of the drugs on cell viability was determined by CellTiter-Glo. Efficacy of LY2606368 in H69 (chemosensitive) and H69/CR (chemoresistant) models was further determined by in vivo flank tumor regression analysis. The effect of LY2606368 monotherapy was also tested in a spontaneous SCLC genetically engineered mouse model (GEMM) model. The mechanistic studies were conducted by immunoblot analysis, a...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Sen, T., Tong, P., Stewart, C. A., Cristea, S., Hong-Fan, Y., Glisson, B. S., Gibbons, D. L., Sage, J., Wang, J., Byers, L. A. Tags: Managing G2/M Control: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA10: The senescence response - yin and yang
Cellular senescence is a stress response that irreversibly arrests cell proliferation and engages a complex senescence-associated secretory phenotype (SASP). The senescence growth arrest prevents the development of cancer by halting cells at risk for malignant transformation. The SASP, which comprises numerous cytokines, chemokines, growth factors, proteases and small metabolites, serves to optimize tissue repair and regeneration in the face of damage. Despite these beneficial effects, the SASP can be deleterious, especially when senescent cells are chronically present such as when they accumulate during aging and at sites...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Campisi, J. Tags: Getting out of Cycle: G0 and Senescence: Oral Presentations - Invited Abstracts Source Type: research

Abstract A10: A Cdk4-dependent phosphorylation threshold regulates the cell cycle entry decision
Cyclin-dependent kinases (Cdk's) are major cell cycle regulators and uncontrolled cell cycle entry is a hallmark of cancer. Cyclin D, the regulatory subunit of Cdk4, is misregulated in about 75% of human malignancies, leading to hyperactive Cdk4 and uncontrolled cell cycle entry. In sharp contrast, the total loss of Cyclin D-mediated activity results in permanent cell cycle arrest. Several functions of Cdk4 during cell cycle entry have been identified; however, the underlying mechanism for cell cycle arrest upon its inactivation remains unanswered. Here we employed CRISPR/Cas9 and rAAV-mediated gene editing to visualize Re...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Kaulich, M., Dowdy, S. Tags: Targeting CDK/cyclins: Hormone Dependent Cancers and Beyond: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR09: c-MYC preserves genomic integrity during DNA replication: a paradigm shift of c-MYC
In this study, we show that the c-MYC transcription factor, which promotes DNA replication, concomitantly stimulates ataxia telangiectasia mutated kinase (ATM), H2AX formation, and DSB repair by repressing BIN1. As an E2F1 corepressor, BIN1 suppressed the human ATM promoter, whereas via protein-protein interaction, BIN1 negatively regulated ATM auto-phosphorylation at serine 1981, a critical step for ATM activation. Accordingly, even before DSBs were formed, impaired BIN1 was sufficient to enhance ATM-dependent phosphorylation of histone H2AX at serine 139 (forming H2AX), which has been widely used as a biomarker of DSBs. ...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Kumari, A., Iwasaki, T., Folk, W. P., Abdulovic-Cui, A. L., Pyndiah, S., Prendergast, G. C., Sedivy, J. M., Sakamuro, D. Tags: Replication Stress and DNA Damage Response: Poster Presentations - Proffered Abstracts Source Type: research

Abstract IA09: A drug delivery method selective for senescent cells
The accumulation of senescent cells occurs in multiple human degenerative pathologies and are also present within tumors. Senescent cells, although not proliferating, are very active in secreting cytokines that may fuel the growth of tumor cells. Therefore, the selective elimination of senescent cells may bring benefits to the treatment of many diseases, including cancer. I will present a strategy to selective deliver drugs to senescent cells in vivo.Citation Format: Manuel Serrano. A drug delivery method selective for senescent cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - T...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Serrano, M. Tags: Getting out of Cycle: G0 and Senescence: Oral Presentations - Invited Abstracts Source Type: research

Abstract IA08: Reprogramming human cancer cells in CDK4/6 inhibitor therapy
CDK4 and CDK6 drive cell cycle progression through early G1 and are frequently deregulated in human cancer. Selective inhibition of CDK4/6 with palbociclib (PD 0332991) has demonstrated exciting clinical efficacy in diverse human cancers. However, the mechanism that discriminates sensitivity from resistance to targeting CDK4/6 remains obscure.Mantle cell lymphoma (MCL) is an incurable non-Hodgkin's lymphoma where deregulated CDK4 activity and cyclin D1 expression underlies unrestrained proliferation and disease progression. In a phase I clinical trial in recurrent MCL, we demonstrated that palbociclib alone produced a dura...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Chen-Kiang, S., Liberto, M. D., Vijay, P., Chiron, D., Huang, X., Ely, S., Elemento, O., Mason, C., Cantley, L., Leonard, J. P., Martin, P. Tags: Targeting CDK/cyclins: Hormone Dependent Cancers and Beyond: Oral Presentations - Invited Abstracts Source Type: research