Abstract B08: Retinoblastoma protein orchestrates cellular apoptosis in non-small cell lung cancer in response to CDK4/6 inhibition: novel targets and key mechanisms
Conclusion: Data from multiple isogenic NSCLC models demonstrate that RB activation via CDK4/6 inhibitors results in apoptosis in an RB dependent manner. Mechanistically, RB represses transcription of multiple IAPs (including FOXM1 and Survivin), which allows pro-apoptotic factors such as SMAC to activate Caspase-3. These findings suggest that CDK4/6 inhibitors should be viewed as cytotoxic, as opposed to purely cytostatic, agents and warrant further clinical investigation.Citation Format: Chellappagounder Thangavel, Ettickan Boopathi, Yi Liu, Alex Haber, Maryna Perepelyuk, Sankar Addya, Sunday Shoyele, Adam P. Dicker, Kar...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Thangavel, C., Boopathi, E., Liu, Y., Haber, A., Perepelyuk, M., Addya, S., Shoyele, S., Dicker, A. P., Knudsen, K. E., Den, R. B. Tags: Rb Bench to Bedside: Novel Functions and Clinical Implications: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A08: Mechanistic basis of Palbociclib combinatorial activity in ER+ breast cancer and non-breast indications
Phosphorylation of the retinoblastoma protein (Rb) by cyclin-dependent kinases 4 and 6 (CDK4/6) is a critical checkpoint for G1/S cell cycle progression and commitment to cellular proliferation. Human malignancies often subvert these control mechanisms through a range of genetic and biochemical adaptations. Accordingly, tumors that depend on CDK4/6 activity for proliferation and survival are particularly sensitive to inhibition of this pathway by palbociclib (Ibrance™), a highly selective inhibitor of CDK4/6 kinase activities. Treatment regimen of palbociclib with letrozole significantly improved progression-free sur...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Dann, S., Chionis, J., Choating, L., Chen, E., Wei, P., Eisele, K., Shields, D. J., Rejto, P. A., VanArsdale, T. Tags: Targeting CDK/cyclins: Hormone Dependent Cancers and Beyond: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR07: Recruitment of Pontin/Reptin by E2F1 amplifies E2F transcriptional response during cancer progression
Unrestricted E2F activity and increased E2F1 expression are hallmarks of liver cancer, but the consequences of aberrant E2F activity for liver cancer progression remain ill defined. Our data show that aberrant E2f activity, following inactivation of the Rb gene family in a mouse model of liver cancer, initially triggers a robust gene expression program associated with the cell cycle and predominantly driven by E2f2 and E2f3. During liver cancer progression, slowly accumulating E2f1 recruits a Pontin/Reptin complex to insert the H2a.z histone variant and open the chromatin conformation at E2f1-bound target genes. This epige...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Tarangelo, A., Lo, N., Teng, R., Kim, E., Raman, P., Viatour, P. Tags: E2F Family Functions: Alterations and Consequences: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA07: Targeting the cyclin D-CDK4/6 pathway for cancer therapy
The cyclin D-CDK4/6 kinase complex plays a pivotal role in the stimulation of cellular proliferation through phosphorylation and functional inactivation of the retinoblastoma protein (pRb), which leads to commitment of G1-phase cells to enter S phase, and ultimately to complete the mitotic cell cycle. Cancer cells frequently escape normal constraints on cell proliferation via persistent inactivation of pRb, through dysregulation of cyclin D-CDK4/6 kinase activity or loss of pRb expression. Interestingly, estrogen-positive (ER+) breast cancer cells rarely show loss of pRb, and hence rely on inappropriate activation of cycli...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Abraham, R. T. Tags: Targeting CDK/cyclins: Hormone Dependent Cancers and Beyond: Oral Presentations - Invited Abstracts Source Type: research

Abstract A07: The identification of combinations for the CDK4 and CDK6 inhibitor, abemaciclib
We developed a combination screening protocol to look for synergistic interactions with abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6 (CDK4 and CDK6). Abemaciclib (LY2835219), has shown cytostatic effects in some cell lines while inducing senescence and apoptosis in particularly sensitive cell lines. Abemaciclib, combined with various compounds, was screened across panels of genomically characterized tumor cells. These screens identified several synergistic interactions that improved the activity of abemaciclib in cancer cells lines that respond to abemaciclib monotherapy (e.g. mantle cell lymphoma, ER+ bre...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Xueqian, G., Chio, L.-C., Webster, Y., Lallena, M. J., Boehnke, K., Torres, R., Iversen, P., Dios, A. D., Smith, I., Reinhard, C., Peng, S.-B., Dempsey, J., Burke, T., Chen, S.-H., Stewart, T., Beckmann, R., Wu, W., Buchanan, S. G. Tags: Targeting CDK/cyclins: Hormone Dependent Cancers and Beyond: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR06: Sox2 functions as a critical oncogene in Rb loss initiated tumors
Tumor suppressors, while important proteins to in the context of tumor formation, are difficult to target for therapeutic purposes. The Rb tumor suppressor, which is lost or functionally inactivated in nearly every human tumor type, is not unique in that regard because restoration of the loss of Rb function has been challenging. Using cellular reprogramming to iPS cells as a model for tumor formation, we identified Sox2 as a direct target of Rb repression. Sox2 is a core pluripotency member with strong reprogramming abilities, and as such, is a potent oncogene in some cellular contexts. Using mouse genetics and genomic ana...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Kareta, M. S., O'Brien, M., Wernig, M., Sage, J. Tags: Rb Bench to Bedside: Novel Functions and Clinical Implications: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA06: Co-Targeting cell cycle and androgen signaling to personalize therapy for hormone dependent prostate cancer
Prostate cancer (PC) is an androgen driven and dependent disease and androgen deprivation therapy (ADT) is the standard for patients with metastatic hormone sensitive disease. Despite a high response rate, most patients will progress to castration resistance. The expanding molecular knowledge highlights the biologic heterogeneity and adaptive capacity of PC, and provides the rationale for a preemptive multi-targeted therapeutic strategy. Compelling support for the latter strategy is provided by recent data from two randomized trials demonstrating an unprecedented impact on survival with the addition of docetaxel to ADT.And...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Hussain, M., Palmbos, P. L., Tomlins, S. A., Daignault-Newton, S., Agarwal, N., Twardowski, P., Morgans, A. K., Antonarakis, E. S., Knudsen, K. E., Feng, F. Y. Tags: Targeting CDK/cyclins: Hormone Dependent Cancers and Beyond: Oral Presentations - Invited Abstracts Source Type: research

Abstract B06: Single-cell RNA-seq profiling of transcriptional transition states during human retinoblastoma development
Retinoblastoma is a rare childhood tumor initiated by biallelic inactivation of the RB1 gene and loss of function of retinoblastoma (Rb) protein. Although Rb loss is a key-initiating event, the molecular mechanisms controlling the transformation into malignancy remain unclear. In this project, we seek to define the cell state transitions that follow RB1 inactivation in a defined cell of origin, the cone photoreceptor precursor. Previously we revealed that Rb knockdown could induce cone precursors to proliferate in vitro and to form retinoblastoma-like tumors in orthotopic xenografts. Using post-mitotic cone precursors from...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Lee, S., Singh, H., Cobrinik, D. Tags: Rb Bench to Bedside: Novel Functions and Clinical Implications: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR05: RB localizes to DNA double strand breaks and promotes DNA end resection and homologous recombination through the recruitment of SWI/SNF complex
The retinoblastoma (RB) tumor suppressor is widely recognized as a master regulator of the transcriptional program that controls entry into the S phase of the cell cycle. RB works by binding to members of the E2F family of transcription factors and recruiting chromatin-remodelers and modifiers to the promoters of E2F target genes. Here we show that RB localizes to DNA double strand breaks (DSBs) dependent on E2F1 and ATM kinase activity. Moreover, RB promotes DNA end resection and homologous recombination, and its loss results in genome instability. RB mediates this important role in repair by recruiting the SWI/SNF chroma...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Velez-Cruz, R., Manickavinayaham, S., Biswas, A. K., Clary, R. W., Johnson, D. G. Tags: Rb Bench to Bedside: Novel Functions and Clinical Implications: Oral Presentations - Proffered Abstracts Source Type: research

Abstract PR04: Characterizing the sequence of cell-cycle events during proliferation and quiescence
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR04) of the Conference Proceedings.Although the cell-cycle field has identified most of the key biochemical events involved in cell-cycle progression, we do not have a clear picture of overall cell-cycle dynamics. The prevalence of cell-to-cell variability is increasingly appreciated, but this heterogeneity is blurred when bulk analysis approaches are used, potentially resulting in incorrect interpretations of biological data. Using a live-cell sensor for CDK2 activity, we recently dis...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Gookin, S., Spencer, S. L. Tags: G1 Advances: Novel Insights into G1 CDK/cyclins: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA04: The Targeting of CDK4/6: Have we gone full circle?
In this study Palbociclib (Palbo) improved median progression free survival (mPFS) from 10.2 months with letrozole alone to 20.2 months with Palbo in the combination therapy [Hazard Ratio (HR) 0.488 (95% CI 0.319, 0.748)]. Response rates were 55.4% with the combination and 39.4% with letrozole alone. Palbo has been tested in other disease including dedifferentiated and well-differentiated liposarcoma where CDK4 is amplified. In this disease Palbo has been reported to increase the PFS at 12 weeks to 66% surpassing the primary end of 40% in patients who had progressed on at least one primary regimen. The major toxicity is ne...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Schwartz, G. K. Tags: G1 Advances: Novel Insights into G1 CDK/cyclins: Oral Presentations - Invited Abstracts Source Type: research

Abstract B04: Novel Methods to Target RB Pathway Disruption in Osteosarcoma
Osteosarcoma, prevalently a pediatric disease, is the most common primary non-hematologic bone tumor. The five-year survival rates range from 24-62% depending on age. A deeper understanding of the disease and new therapeutic approaches are crucial to reducing osteosarcoma's morbidity and mortality.Data from our and other laboratories point to interconnections between bone development and cancer. Specifically, RB1 gene mutation (encoding retinoblastoma protein or pRB) is observed in 60% of sporadic osteosarcomas, and the pRB pathway is altered in osteosarcomas that retain pRB function. Mouse data suggests that loss of pRB c...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Hinds, P. W., Enos, M., Kong, E., Dignan, E., Gunduz, V., Pietruska, J. Tags: Rb Bench to Bedside: Novel Functions and Clinical Implications: Poster Presentations - Proffered Abstracts Source Type: research

Abstract PR03: Extended inhibition of CDK4/6 inhibits mTORC1 signaling and induces therapeutic senescence in vemurafenib resistant melanoma
Dysregulation of the p16-cyclin D1-CDK4/6-Rb pathway occurs frequently in melanoma; however, the therapeutic efficacy of CDK4/6 inhibition remains to be critically evaluated. We demonstrate that CDK4/6 inhibition inhibits melanoma progression through induction of senescence. Palbociclib, a specific CDK4/6 inhibitor, rapidly induces cell cycle within 24h and continued exposure for 8-days or longer induces senescence. The induction of senescence correlates with inhibition of mTOR and more specifically mTORC1 signaling. Vemurafenib, a specific BRAFV600E inhibitor, has significant clinical efficacy in BRAFV600E positive melano...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Yoshida, A., Diehl, J. A. Tags: Targeting CDK/cyclins: Hormone Dependent Cancers and Beyond: Oral Presentations - Proffered Abstracts Source Type: research

Abstract B03: Physical and functional interactions between two tumor suppressors, BIN1 and RB1
The bridging integrator 1 (BIN1) protein was originally identified as a cellular adaptor protein that interacts with the transcription factor c-MYC and inhibits cell proliferation. However, BIN1 inhibits tumor cell growth by both a BIN1 MYC-binding domain (MBD)-dependent mechanism and an MBD-independent mechanism. Consistently, BIN1 promotes skeletal muscle differentiation in vitro where c-MYC is not detectable, suggesting that an undefined BIN1-interacting protein other than c-MYC determines BIN1-mediated growth arrest in an MYC-independent manner.Here we show the functional interplay between BIN1 and the RB1 tumor suppre...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Folk, W. P., Kumari, A., Cassimere, E., Johnson, J., Sakamuro, D. Tags: Rb Bench to Bedside: Novel Functions and Clinical Implications: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A03: SCFCyclin F connects AKT signaling to the core cell cycle oscillator
Cell proliferation is governed by the presence of growth factors, and in their absence normal cells cease to progress through the cell cycle. The waves of Cyclin Dependent Kinase (CDK) activity constituting the core of the cell cycle oscillator are driven by cyclin synthesis and its subsequent destruction by the Anaphase Promoting Complex/Cyclosome (APC), a multi-subunit E3 ubiquitin ligase that controls degradation of Cyclins A and B. How growth factor signaling is integrated into the core cell cycle machinery remains largely elusive. Modular Cullin RING ubiquitin ligases (CRLs) represent the largest E3 ligase family in h...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Emanuele, M. J., Choudhury, R., Kernan, J., Mills, C. A., Lahiri, D., Burke, D. J. Tags: G1 Advances: Novel Insights into G1 CDK/cyclins: Oral Presentations - Proffered Abstracts Source Type: research

Abstract IA02: Neomorphic functions of cyclin D1 during neoplastic development
Cyclin D1 is a cell cycle recipient of diverse oncogenic signals and a multifunctional transcriptional modulator. Extensive studies have characterized mutational disruption of p53 signaling in human cancers. However, the mechanisms underlying retention of wild-type p53 during neoplastic outgrowth have remained ambiguous. We have identified and functionally validated a crucial role for arginine-methylation of p53 as a mechanism for inhibition of p53-dependent apoptosis in response to oncogenic insults. Phosphorylation-dependent activation of PRMT5/MEP50 enforces catalytic targeting of p53 thereby reducing p53 occupancy on k...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Diehl, J. A. Tags: G1 Advances: Novel Insights into G1 CDK/cyclins: Oral Presentations - Invited Abstracts Source Type: research

Abstract A02: Cyclin A2 and CDK2 as Novel Targets of Aspirin and Salicylic acid: a Potential Role in Cancer Prevention
In this study, HT-29 and other diverse panel of cancer cells were used to demonstrate that both aspirin and its primary metabolite, salicylic acid, decreased cyclin A2 (CCNA2) and CDK2 protein and mRNA levels. The down regulatory effect of either drugs on cyclin A2 levels was prevented by pretreatment with lactacystin, an inhibitor of proteasomes, suggesting the involvement of 26S proteasomes. In-vitro kinase assays showed that lysates from cells treated with salicylic acid had lower levels of CDK2 activity. Importantly, three independent experiments revealed that salicylic acid directly binds to CDK2. Firstly, inclusion o...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Dachineni, R., Ai, G., D, R. K., Sadhu, S., Tummala, H., Gunaje, J. B. Tags: G1 Advances: Novel Insights into G1 CDK/cyclins: Oral Presentations - Proffered Abstracts Source Type: research

Abstract PR01: Therapeutic targeting of cdk4 in bladder cancer
Bladder cancer (BC) is a current clinical and social problem. At diagnosis, 70% of the patients display non-muscle invasive tumor (NMIBC), a relatively indolent disease treated by transurethral resection followed by local instillation in some cases. Unfortunately, NMIBC displays an extremely high recurrence rate, and these recurrent tumors may display tumor progression showing muscle invasive (MIBC) characteristics. MIBC is treated, in most cases, by cystectomy and platinum-based chemotherapy. Nonetheless, the metastatic spreading occurs very often with fatal consequences. Various targeted therapies are being clinically an...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Rubio, C., Lopez-Calderon, F., Segovia, C., Duenas, M., Martinez-Fernandez, M., Otero, I., Rosa, F. d. l., Villacampa, F., Castellano, D., Paramio, J. M. Tags: G1 Advances: Novel Insights into G1 CDK/cyclins: Oral Presentations - Proffered Abstracts Source Type: research

Abstract B01: pRb activates mitochondrial metabolism and promotes differentiation through the histone demethylase Kdm5a
We present the evidence that Rb1-deficient MEFs have a decreased oxidative capacity compared to the wild type MEFs, while loss of Kdm5a results in a highly increased respiration and TCA cycle metabolites. Overexpression of Pgc-1α and Mfn2 increased oxidative capacity in parallel with the differentiation rescue. In contrast, knockdown of Mfn2 inhibited oxidation as well as differentiation. Similar experiments conducted in Pgc-1α-/- MEFs were consistent with the role for Pgc-1α in increasing oxidative capacity. The data on establishing the link between mitochondrial function and differentiation are importan...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Varaljai, R., Islam, A. B. M. M. K., Dyson, N. J., Benevolenskaya, E. V. Tags: Rb Bench to Bedside: Novel Functions and Clinical Implications: Poster Presentations - Proffered Abstracts Source Type: research

Abstract A01: Trichodermin induces G1/S cell cycle arrest in ovarian cancer cells
In this study, A2780/CP70 and OVCAR-3 ovarian cancer cell lines were treated with trichodermin to determine whether it had an anti-cancer effect. Our data presented that trichodermin reduced the viability of both ovarian cancer cells by inducing G1/S cell cycle arrest rather than apoptosis. The underlying mechanism might be that trichodermin down-regulated the expression of Cyclin D1 via inhibiting AhR and c-Myc expression. Therefore, trichodermin is promising in ovarian cancer treatment.Citation Format: Yi C. Chen, Ying Gao. Trichodermin induces G1/S cell cycle arrest in ovarian cancer cells. [abstract]. In: Proceedings o...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Chen, Y. C., Gao, Y. Tags: G1 Advances: Novel Insights into G1 CDK/cyclins: Oral Presentations - Proffered Abstracts Source Type: research

Melatonin Represses Metastasis in Her2-Postive Human Breast Cancer Cells by Suppressing RSK2 Expression
The importance of the circadian/melatonin signal in suppressing the metastatic progression of breast and other cancers has been reported by numerous laboratories including our own. Currently, the mechanisms underlying the antimetastatic actions of melatonin have not been well established. In the present study, the antimetastatic actions of melatonin were evaluated and compared on the ERα-negative, Her2-positive SKBR-3 breast tumor cell line and ERα-positive MCF-7 cells overexpressing a constitutively active HER2.1 construct (MCF-7Her2.1 cells). Activation of Her2 is reported to induce the expression and/or phos...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Mao, L., Summers, W., Xiang, S., Yuan, L., Dauchy, R. T., Reynolds, A., Wren-Dail, M. A., Pointer, D., Frasch, T., Blask, D. E., Hill, S. M. Tags: Signal Transduction Source Type: research

Systemic Ablation of MMP-9 Triggers Invasive Growth and Metastasis of Pancreatic Cancer via Deregulation of IL6 Expression in the Bone Marrow
In conclusion, ablation of systemic MMP-9 initiated fatal communication between maintenance of physiological functions of MMP-9 in the bone marrow and invasive growth of PDAC via the IL6/IL6R/STAT3 axis. Implications: Thus, the beneficial effects of host MMP-9 on PDAC are an important caveat for the use of systemic MMP-9 inhibitors in cancer. Mol Cancer Res; 14(11); 1147–58. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Grünwald, B., Vandooren, J., Gerg, M., Ahomaa, K., Hunger, A., Berchtold, S., Akbareian, S., Schaten, S., Knolle, P., Edwards, D. R., Opdenakker, G., Krüger, A. Tags: Signal Transduction Source Type: research

Exosome-mediated Transfer of {alpha}v{beta}3 Integrin from Tumorigenic to Nontumorigenic Cells Promotes a Migratory Phenotype
The αvβ3 integrin is known to be highly upregulated during cancer progression and promotes a migratory and metastatic phenotype in many types of tumors. We hypothesized that the αvβ3 integrin is transferred through exosomes and, upon transfer, has the ability to support functional aberrations in recipient cells. Here, for the first time, it is demonstrated that αvβ3 is present in exosomes released from metastatic PC3 and CWR22Pc prostate cancer cells. Exosomal β3 is transferred as a protein from donor to nontumorigenic and tumorigenic cells as β3 protein or mRNA levels remain unaf...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Singh, A., Fedele, C., Lu, H., Nevalainen, M. T., Keen, J. H., Languino, L. R. Tags: Signal Transduction Source Type: research

Inhibition of S-Adenosylmethionine-Dependent Methyltransferase Attenuates TGF{beta}1-Induced EMT and Metastasis in Pancreatic Cancer: Putative Roles of miR-663a and miR-4787-5p
The identification of epigenetic reversal agents for use in combination chemotherapies to treat human pancreatic ductal adenocarcinomas (PDAC) remains an unmet clinical need. Pharmacologic inhibitors of Enhancer of Zeste Homolog 2 (EZH2) are emerging as potential histone methylation reversal agents for the treatment of various solid tumors and leukemia; however, the surprisingly small set of mRNA targets identified with EZH2 knockdown suggests novel mechanisms contribute to their antitumorigenic effects. Here, 3-deazaneplanocin-A (DZNep), an inhibitor of S-adenosyl-L-homocysteine hydrolase and EZH2 histone lysine-N-methylt...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Mody, H. R., Hung, S. W., AlSaggar, M., Griffin, J., Govindarajan, R. Tags: Oncogenes and Tumor Suppressors Source Type: research

Ubiquitin Ligase, Fbw7, Targets CDX2 for Degradation via Two Phosphodegron Motifs in a GSK3{beta}-Dependent Manner
Drosophila caudal–related homeobox transcription factor 2 (CDX2) drives differentiation of the intestinal epithelium. Loss of CDX2 expression has been reported in several colorectal cancers and cancer cell lines with a potential inverse correlation between CDX2 levels and tumor stage. Ubiquitination of CDX2 leading to its downregulation has been implicated in several studies; however, the E3 ubiquitin ligases involved in CDX2 ubiquitination have largely remained unknown. Here, it is mechanistically determined that the E3 ubiquitin ligase Fbw7 promotes CDX2 ubiquitination and degradation through two phosphodegron moti...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Kumar, Y., Shukla, N., Thacker, G., Kapoor, I., Lochab, S., Bhatt, M. L. B., Chattopadhyay, N., Sanyal, S., Trivedi, A. K. Tags: Oncogenes and Tumor Suppressors Source Type: research

Extracellular ATP a New Player in Cancer Metabolism: NSCLC Cells Internalize ATP In Vitro and In Vivo Using Multiple Endocytic Mechanisms
Intratumoral extracellular ATP concentrations are 1000 times higher than those in normal tissues of the same cell origin. However, whether or not cancer cells use the abundant extracellular ATP was unknown until we recently reported that cancer cells internalize ATP. The internalized ATP was found to substantially increase intracellular ATP concentration and promote cell proliferation and drug resistance in cancer cells. Here, using a nonhydrolyzable fluorescent ATP (NHF-ATP), radioactive and regular ATP, coupled with high and low molecular weight dextrans as endocytosis tracers and fluorescence microscopy and ATP assays, ...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Qian, Y., Wang, X., Li, Y., Cao, Y., Chen, X. Tags: Metabolism Source Type: research

Transcription Factor KLF5 Binds a Cyclin E1 Polymorphic Intronic Enhancer to Confer Increased Bladder Cancer Risk
It is well established that environmental toxins, such as exposure to arsenic, are risk factors in the development of urinary bladder cancer, yet recent genome-wide association studies (GWAS) provide compelling evidence that there is a strong genetic component associated with disease predisposition. A single-nucleotide polymorphism (SNP), rs8102137, was identified on chromosome 19q12, residing 6 kb upstream of the important cell-cycle regulator and proto-oncogene, Cyclin E1 (CCNE1). However, the functional role of this variant in bladder cancer predisposition has been unclear because it lies within a non-coding region of t...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Pattison, J. M., Posternak, V., Cole, M. D. Tags: Genomics Source Type: research

Estrogen Drives Cellular Transformation and Mutagenesis in Cells Expressing the Breast Cancer-Associated R438W DNA Polymerase Lambda Protein
Repair of DNA damage is critical for maintaining the genomic integrity of cells. DNA polymerase lambda (POLL/Pol ) is suggested to function in base excision repair (BER) and nonhomologous end-joining (NHEJ), and is likely to play a role in damage tolerance at the replication fork. Here, using next-generation sequencing, it was discovered that the POLL rs3730477 single-nucleotide polymorphism (SNP) encoding R438W Pol was significantly enriched in the germlines of breast cancer patients. Expression of R438W Pol in human breast epithelial cells induces cellular transformation and chromosomal aberrations. The role of estrogen ...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Nemec, A. A., Bush, K. B., Towle-Weicksel, J. B., Taylor, B. F., Schulz, V., Weidhaas, J. B., Tuck, D. P., Sweasy, J. B. Tags: DNA Damage and Repair Source Type: research

Cooperative Dynamics of AR and ER Activity in Breast Cancer
This study suggests that AR plays a previously unrecognized role in supporting E2-mediated ER activity in ER+/AR+ breast cancer cells, and that enzalutamide may be an effective therapeutic in ER+/AR+ breast cancers. Mol Cancer Res; 14(11); 1054–67. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: D'Amato, N. C., Gordon, M. A., Babbs, B., Spoelstra, N. S., Carson Butterfield, K. T., Torkko, K. C., Phan, V. T., Barton, V. N., Rogers, T. J., Sartorius, C. A., Elias, A., Gertz, J., Jacobsen, B. M., Richer, J. K. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

Induction of PSMA and Internalization of an Anti-PSMA mAb in the Vascular Compartment
Angiogenesis is critical for tumor growth and survival and involves interactions between cancer and endothelial cells. Prostate-specific membrane antigen (PSMA/FOLH1) is expressed in the neovasculature of several types of cancer. However, the study of neovascular PSMA expression has been impeded as human umbilical vein endothelial cell (HUVEC) cultures are PSMA-negative and both tumor xenografts and patient-derived xenograft (PDX) models are not known to express PSMA in their vasculature. Therefore, PSMA expression was examined in HUVECs, in vitro and in vivo, and we tested the hypothesis that cancer cell–HUVEC cross...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Nguyen, D. P., Xiong, P. L., Liu, H., Pan, S., Leconet, W., Navarro, V., Guo, M., Moy, J., Kim, S., Ramirez-Fort, M. K., Batra, J. S., Bander, N. H. Tags: Cell Death and Survival Source Type: research

Rnd3 in Cancer: A Review of the Evidence for Tumor Promoter or Suppressor
Rho-GTPases are members of the Ras superfamily of small GTPases and are general modulators of important cellular processes in tumor biology such as migration and proliferation. Among these proteins, Rnd3/RhoE, an atypical Rho-GTPase devoid of GTP hydrolytic activity, has recently been studied for its putative role in tumorigenesis. Indeed, Rnd3 is implicated in processes, such as proliferation and migration, whose deregulation is linked to cancer development and metastasis. The aim of this review is to provide an overview of the data surrounding Rnd3 deregulation in cancers, its origin, and consequences. Presented here is ...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Paysan, L., Piquet, L., Saltel, F., Moreau, V. Tags: Review Source Type: research

Highlights of This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Tags: Highlights Source Type: research

Melatonin Represses Rsk of Breast Cancer Metastasis
The importance of the circadian/melatonin signal in suppressing the metastatic progression of breast and other cancers has been reported by numerous laboratories including our own. Currently, the mechanisms underlying the antimetastatic actions of melatonin have not been well established. In the present study, the antimetastatic actions of melatonin were evaluated and compared on the ERα-negative, Her2-positive SKBR-3 breast tumor cell line and ERα-positive MCF-7 cells overexpressing a constitutively active HER2.1 construct (MCF-7Her2.1 cells). Activation of Her2 is reported to induce the expression and/or phos...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Mao, L., Summers, W., Xiang, S., Yuan, L., Dauchy, R. T., Reynolds, A., Wren-Dail, M. A., Pointer, D., Frasch, T., Blask, D. E., Hill, S. M. Tags: Signal Transduction Source Type: research

MMP-9 Ablation-Induced Invasive Growth of PDAC
In conclusion, ablation of systemic MMP-9 initiated fatal communication between maintenance of physiological functions of MMP-9 in the bone marrow and invasive growth of PDAC via the IL6/IL6R/STAT3 axis. Implications: Thus, the beneficial effects of host MMP-9 on PDAC are an important caveat for the use of systemic MMP-9 inhibitors in cancer. Mol Cancer Res; 14(11); 1147–58. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Grünwald, B., Vandooren, J., Gerg, M., Ahomaa, K., Hunger, A., Berchtold, S., Akbareian, S., Schaten, S., Knolle, P., Edwards, D. R., Opdenakker, G., Krüger, A. Tags: Signal Transduction Source Type: research

Exosome-mediated Transfer of {alpha}v{beta}3 Integrin
The αvβ3 integrin is known to be highly upregulated during cancer progression and promotes a migratory and metastatic phenotype in many types of tumors. We hypothesized that the αvβ3 integrin is transferred through exosomes and, upon transfer, has the ability to support functional aberrations in recipient cells. Here, for the first time, it is demonstrated that αvβ3 is present in exosomes released from metastatic PC3 and CWR22Pc prostate cancer cells. Exosomal β3 is transferred as a protein from donor to nontumorigenic and tumorigenic cells as β3 protein or mRNA levels remain unaf...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Singh, A., Fedele, C., Lu, H., Nevalainen, M. T., Keen, J. H., Languino, L. R. Tags: Signal Transduction Source Type: research

DZNep Resists EMT of Pancreatic Cancer via miRNAs
The identification of epigenetic reversal agents for use in combination chemotherapies to treat human pancreatic ductal adenocarcinomas (PDAC) remains an unmet clinical need. Pharmacologic inhibitors of Enhancer of Zeste Homolog 2 (EZH2) are emerging as potential histone methylation reversal agents for the treatment of various solid tumors and leukemia; however, the surprisingly small set of mRNA targets identified with EZH2 knockdown suggests novel mechanisms contribute to their antitumorigenic effects. Here, 3-deazaneplanocin-A (DZNep), an inhibitor of S-adenosyl-L-homocysteine hydrolase and EZH2 histone lysine-N-methylt...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Mody, H. R., Hung, S. W., AlSaggar, M., Griffin, J., Govindarajan, R. Tags: Oncogenes and Tumor Suppressors Source Type: research

Fbw7 Negatively Regulates CDX2 Stability
Drosophila caudal–related homeobox transcription factor 2 (CDX2) drives differentiation of the intestinal epithelium. Loss of CDX2 expression has been reported in several colorectal cancers and cancer cell lines with a potential inverse correlation between CDX2 levels and tumor stage. Ubiquitination of CDX2 leading to its downregulation has been implicated in several studies; however, the E3 ubiquitin ligases involved in CDX2 ubiquitination have largely remained unknown. Here, it is mechanistically determined that the E3 ubiquitin ligase Fbw7 promotes CDX2 ubiquitination and degradation through two phosphodegron moti...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Kumar, Y., Shukla, N., Thacker, G., Kapoor, I., Lochab, S., Bhatt, M. L. B., Chattopadhyay, N., Sanyal, S., Trivedi, A. K. Tags: Oncogenes and Tumor Suppressors Source Type: research

NSCLC Tumors Endocytotically Engulf ATP
Intratumoral extracellular ATP concentrations are 1000 times higher than those in normal tissues of the same cell origin. However, whether or not cancer cells use the abundant extracellular ATP was unknown until we recently reported that cancer cells internalize ATP. The internalized ATP was found to substantially increase intracellular ATP concentration and promote cell proliferation and drug resistance in cancer cells. Here, using a nonhydrolyzable fluorescent ATP (NHF-ATP), radioactive and regular ATP, coupled with high and low molecular weight dextrans as endocytosis tracers and fluorescence microscopy and ATP assays, ...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Qian, Y., Wang, X., Li, Y., Cao, Y., Chen, X. Tags: Metabolism Source Type: research

KLF5 and Cyclin E1 Confer Bladder Cancer Risk
It is well established that environmental toxins, such as exposure to arsenic, are risk factors in the development of urinary bladder cancer, yet recent genome-wide association studies (GWAS) provide compelling evidence that there is a strong genetic component associated with disease predisposition. A single-nucleotide polymorphism (SNP), rs8102137, was identified on chromosome 19q12, residing 6 kb upstream of the important cell-cycle regulator and proto-oncogene, Cyclin E1 (CCNE1). However, the functional role of this variant in bladder cancer predisposition has been unclear because it lies within a non-coding region of t...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Pattison, J. M., Posternak, V., Cole, M. D. Tags: Genomics Source Type: research

Estrogen Promotes Pol {lambda} Variant-Mediated Genomic Instability
Repair of DNA damage is critical for maintaining the genomic integrity of cells. DNA polymerase lambda (POLL/Pol ) is suggested to function in base excision repair (BER) and nonhomologous end-joining (NHEJ), and is likely to play a role in damage tolerance at the replication fork. Here, using next-generation sequencing, it was discovered that the POLL rs3730477 single-nucleotide polymorphism (SNP) encoding R438W Pol was significantly enriched in the germlines of breast cancer patients. Expression of R438W Pol in human breast epithelial cells induces cellular transformation and chromosomal aberrations. The role of estrogen ...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Nemec, A. A., Bush, K. B., Towle-Weicksel, J. B., Taylor, B. F., Schulz, V., Weidhaas, J. B., Tuck, D. P., Sweasy, J. B. Tags: DNA Damage and Repair Source Type: research

AR Is Required for ER Activity in Breast Cancer
This study suggests that AR plays a previously unrecognized role in supporting E2-mediated ER activity in ER+/AR+ breast cancer cells, and that enzalutamide may be an effective therapeutic in ER+/AR+ breast cancers. Mol Cancer Res; 14(11); 1054–67. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: D'Amato, N. C., Gordon, M. A., Babbs, B., Spoelstra, N. S., Carson Butterfield, K. T., Torkko, K. C., Phan, V. T., Barton, V. N., Rogers, T. J., Sartorius, C. A., Elias, A., Gertz, J., Jacobsen, B. M., Richer, J. K. Tags: Chromatin, Epigenetics, and RNA Regulation Source Type: research

PSMA Induction in Endothelial Cells
Angiogenesis is critical for tumor growth and survival and involves interactions between cancer and endothelial cells. Prostate-specific membrane antigen (PSMA/FOLH1) is expressed in the neovasculature of several types of cancer. However, the study of neovascular PSMA expression has been impeded as human umbilical vein endothelial cell (HUVEC) cultures are PSMA-negative and both tumor xenografts and patient-derived xenograft (PDX) models are not known to express PSMA in their vasculature. Therefore, PSMA expression was examined in HUVECs, in vitro and in vivo, and we tested the hypothesis that cancer cell–HUVEC cross...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Nguyen, D. P., Xiong, P. L., Liu, H., Pan, S., Leconet, W., Navarro, V., Guo, M., Moy, J., Kim, S., Ramirez-Fort, M. K., Batra, J. S., Bander, N. H. Tags: Cell Death and Survival Source Type: research

Understanding Atypical Rho-GTPase Rnd3/RhoE in Cancer
Rho-GTPases are members of the Ras superfamily of small GTPases and are general modulators of important cellular processes in tumor biology such as migration and proliferation. Among these proteins, Rnd3/RhoE, an atypical Rho-GTPase devoid of GTP hydrolytic activity, has recently been studied for its putative role in tumorigenesis. Indeed, Rnd3 is implicated in processes, such as proliferation and migration, whose deregulation is linked to cancer development and metastasis. The aim of this review is to provide an overview of the data surrounding Rnd3 deregulation in cancers, its origin, and consequences. Presented here is ...
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Paysan, L., Piquet, L., Saltel, F., Moreau, V. Tags: Review Source Type: research

Selected Articles from This Issue
(Source: Molecular Cancer Research)
Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Tags: Highlights Source Type: research

Phosphoproteomics Reveals MAPK Inhibitors Enhance MET- and EGFR-Driven AKT Signaling in KRAS-Mutant Lung Cancer
This study highlights the unique adaptive changes in MAPK scaffolding proteins (KSR-1, GEF-H1) and in RTK signaling, leading to enhanced PI3K/AKT signaling when the MAPK pathway is inhibited. Mol Cancer Res; 14(10); 1019–29. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Kim, J.-Y., Welsh, E. A., Fang, B., Bai, Y., Kinose, F., Eschrich, S. A., Koomen, J. M., Haura, E. B. Tags: Signal Transduction Source Type: research

ERK/MAPK Signaling Drives Overexpression of the Rac-GEF, PREX1, in BRAF- and NRAS-Mutant Melanoma
This study identifies an ERK-dependent mechanism that drives PREX1 upregulation and subsequent RAC1-dependent invasion in BRAF- and NRAS-mutant melanoma. Mol Cancer Res; 14(10); 1009–18. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Ryan, M. B., Finn, A. J., Pedone, K. H., Thomas, N. E., Der, C. J., Cox, A. D. Tags: Signal Transduction Source Type: research

HDAC6 Deacetylates HMGN2 to Regulate Stat5a Activity and Breast Cancer Growth
Stat5a is a transcription factor utilized by several cytokine/hormone receptor signaling pathways that promotes transcription of genes associated with proliferation, differentiation, and survival of cancer cells. However, there are currently no clinically approved therapies that directly target Stat5a, despite ample evidence that it contributes to breast cancer pathogenesis. Here, deacetylation of the Stat5a coactivator and chromatin-remodeling protein HMGN2 on lysine residue K2 by HDAC6 promotes Stat5a-mediated transcription and breast cancer growth. HDAC6 inhibition both in vitro and in vivo enhances HMGN2 acetylation wi...
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Medler, T. R., Craig, J. M., Fiorillo, A. A., Feeney, Y. B., Harrell, J. C., Clevenger, C. V. Tags: Signal Transduction Source Type: research

MNK Inhibition Disrupts Mesenchymal Glioma Stem Cells and Prolongs Survival in a Mouse Model of Glioblastoma
Glioblastoma multiforme remains the deadliest malignant brain tumor, with glioma stem cells (GSC) contributing to treatment resistance and tumor recurrence. We have identified MAPK-interacting kinases (MNK) as potential targets for the GSC population in glioblastoma multiforme. Isoform-level subtyping using The Cancer Genome Atlas revealed that both MNK genes (MKNK1 and MKNK2) are upregulated in mesenchymal glioblastoma multiforme as compared with other subtypes. Expression of MKNK1 is associated with increased glioma grade and correlated with the mesenchymal GSC marker, CD44, and coexpression of MKNK1 and CD44 predicts po...
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Bell, J. B., Eckerdt, F. D., Alley, K., Magnusson, L. P., Hussain, H., Bi, Y., Arslan, A. D., Clymer, J., Alvarez, A. A., Goldman, S., Cheng, S.-Y., Nakano, I., Horbinski, C., Davuluri, R. V., James, C. D., Platanias, L. C. Tags: Signal Transduction Source Type: research

Rapid Conversion of Mutant IDH1 from Driver to Passenger in a Model of Human Gliomagenesis
Missense mutations in the active site of isocitrate dehydrogenase 1 (IDH1) biologically and diagnostically distinguish low-grade gliomas and secondary glioblastomas from primary glioblastomas. IDH1 mutations lead to the formation of the oncometabolite 2-hydroxyglutarate (2-HG) from the reduction of α-ketoglutarate (α-KG), which in turn facilitates tumorigenesis by modifying DNA and histone methylation as well blocking differentiation processes. Although mutant IDH1 expression is thought to drive the gliomagenesis process, the extent to which it remains a viable therapeutic target remains unknown. To address thi...
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Johannessen, T.-C. A., Mukherjee, J., Viswanath, P., Ohba, S., Ronen, S. M., Bjerkvig, R., Pieper, R. O. Tags: Oncogenes and Tumor Suppressors Source Type: research

Mitochondrial {beta}-Carotene 9',10' Oxygenase Modulates Prostate Cancer Growth via NF-{kappa}B Inhibition: A Lycopene-Independent Function
This study investigated expression and functional roles of BCO2 in human prostate cancer. Expression of the bco2 gene is dramatically decreased in prostate cancer tissue and in a range of prostate cancer cell lines as compared with nonneoplastic prostate tissue and normal prostatic epithelial cells, respectively. Inhibition of DNA methyltransferase activity restored bco2 expression in prostate cancer cell lines tested. Treatment with lycopene or its metabolite, apo-10-lycopenal, also increased bco2 expression and reduced cell proliferation in androgen-sensitive cell lines, but lycopene neither altered bco2 expression nor c...
Source: Molecular Cancer Research - October 12, 2016 Category: Cancer & Oncology Authors: Gong, X., Marisiddaiah, R., Zaripheh, S., Wiener, D., Rubin, L. P. Tags: Oncogenes and Tumor Suppressors Source Type: research