MUC1-C Represses the Crumbs Complex Polarity Factor CRB3 and Downregulates the Hippo Pathway
Apical–basal polarity and epithelial integrity are maintained in part by the Crumbs (CRB) complex. The C--terminal subunit of MUC1 (MUC1-C) is a transmembrane protein that is expressed at the apical border of normal epithelial cells and aberrantly at high levels over the entire surface of their transformed counterparts. However, it is not known whether MUC1-C contributes to this loss of polarity that is characteristic of carcinoma cells. Here it is demonstrated that MUC1-C downregulates expression of the Crumbs complex CRB3 protein in triple-negative breast cancer (TNBC) cells. MUC1-C associates with ZEB1 on the CRB3...
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: Alam, M., Bouillez, A., Tagde, A., Ahmad, R., Rajabi, H., Maeda, T., Hiraki, M., Suzuki, Y., Kufe, D. Tags: Oncogenes and Tumor Suppressors Source Type: research
Adipose-Induced Retroperitoneal Soft Tissue Sarcoma Tumorigenesis: A Potential Crosstalk between Sarcoma and Fat Cells
The objective of the current study was to evaluate potential paracrine effects of visceral fat on RSTS. A xenograft model was used to evaluate in vivo effects of human visceral fat on STS growth. Tissue explants were prepared from visceral fat, and their conditioned medium (CM) was utilized for various in vitro experiments designed to evaluate growth, survival, migration, and invasion of STS and endothelial cells. Visceral fat–secreted protumorigenic factors were identified by mass spectrometry. The in vivo experiments demonstrated a significant increase in STS tumor growth rate when SK-LMS-1 leiomyosarcoma cells wer...
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: Loewenstein, S., Lubezky, N., Nizri, E., Zemel, M., Levin, Y., Savidor, A., Sher, O., Klausner, J. M., Lahat, G. Tags: Oncogenes and Tumor Suppressors Source Type: research
Heparanase Promotes Glioma Progression and Is Inversely Correlated with Patient Survival
In conclusion, these data provide proof-of-concept for anti-HPSE treatment of malignant glioma, as well as novel insights for the development of HPSE as a therapeutic target.
Implications: This study aims to target both the malignant brain tumor cells per se and their microenvironment by changing the level of an enzyme, HPSE, that breaks down modified sugar chains on cell surfaces and in the extracellular space. Mol Cancer Res; 14(12); 1243–53. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: Kundu, S., Xiong, A., Spyrou, A., Wicher, G., Marinescu, V. D., Edqvist, P.-H. D., Zhang, L., Essand, M., Dimberg, A., Smits, A., Ilan, N., Vlodavsky, I., Li, J.-P., Forsberg-Nilsson, K. Tags: Oncogenes and Tumor Suppressors Source Type: research
Increased Expression of System xc- in Glioblastoma Confers an Altered Metabolic State and Temozolomide Resistance
Glioblastoma multiforme is the most aggressive malignant primary brain tumor in adults. Several studies have shown that glioma cells upregulate the expression of xCT (SLC7A11), the catalytic subunit of system xc–, a transporter involved in cystine import, that modulates glutathione production and glioma growth. However, the role of system xc– in regulating the sensitivity of glioma cells to chemotherapy is currently debated. Inhibiting system xc– with sulfasalazine decreased glioma growth and survival via redox modulation, and use of the chemotherapeutic agent temozolomide together with sulfasalazine had ...
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: Polewski, M. D., Reveron-Thornton, R. F., Cherryholmes, G. A., Marinov, G. K., Cassady, K., Aboody, K. S. Tags: Metabolism Source Type: research
Integrated Genetic, Epigenetic, and Transcriptional Profiling Identifies Molecular Pathways in the Development of Laterally Spreading Tumors
Laterally spreading tumors (LST) are colorectal adenomas that develop into extremely large lesions with predominantly slow progression to cancer, depending on lesion subtype. Comparing and contrasting the molecular profiles of LSTs and colorectal cancers offers an opportunity to delineate key molecular alterations that drive malignant transformation in the colorectum. In a discovery cohort of 11 LSTs and paired normal mucosa, we performed a comprehensive and unbiased screen of the genome, epigenome, and transcriptome followed by bioinformatics integration of these data and validation in an additional 84 large, benign color...
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: Hesson, L. B., Ng, B., Zarzour, P., Srivastava, S., Kwok, C.-T., Packham, D., Nunez, A. C., Beck, D., Ryan, R., Dower, A., Ford, C. E., Pimanda, J. E., Sloane, M. A., Hawkins, N. J., Bourke, M. J., Wong, J. W. H., Ward, R. L. Tags: Genomics Source Type: research
MEK and TAK1 Regulate Apoptosis in Colon Cancer Cells with KRAS-Dependent Activation of Proinflammatory Signaling
This study describes a potential therapeutic strategy for a subset of colon cancers that are dependent on oncogenic KRAS signaling pathways, which are currently difficult to block with selective agents. Mol Cancer Res; 14(12); 1204–16. ©2016 AACR. (Source: Molecular Cancer Research)
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: McNew, K. L., Whipple, W. J., Mehta, A. K., Grant, T. J., Ray, L., Kenny, C., Singh, A. Tags: Cell Death and Survival Source Type: research
Olaparib, Monotherapy or with Ionizing Radiation, Exacerbates DNA Damage in Normal Tissues: Insights from a New p21 Reporter Mouse
Many drugs targeting the DNA damage response are being developed as anticancer therapies, either as single agents or in combination with ionizing radiation (IR) or other cytotoxic agents. Numerous clinical trials in this area are either in progress or planned. However, concerns remain about the potential of such treatments to increase toxicity to normal tissues. In order to address this issue, a novel reporter mouse line was created through the simultaneous incorporation of multiple reporters, β-galactosidase, and firefly luciferase, into the DNA damage–inducible p21 (CDKN1A) locus. The data demonstrate that in ...
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: McMahon, M., Frangova, T. G., Henderson, C. J., Wolf, C. R. Tags: DNA Damage and Repair Source Type: research
AMPK{alpha}2 Regulates Bladder Cancer Growth through SKP2-Mediated Degradation of p27
AMP-activated protein kinase (AMPK) is the central metabolic regulator of the cell and controls energy consumption based upon nutrient availability. Due to its role in energy regulation, AMPK has been implicated as a barrier for cancer progression and is suppressed in multiple cancers. To examine whether AMPK regulates bladder cancer cell growth, HTB2 and HT1376 bladder cells were treated with an AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). AICAR treatment reduced proliferation and induced the expression of p27Kip1 (CDKN1B), which was mediated through an mTOR-dependent mechanism. Interestingly, AM...
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: Kopsiaftis, S., Sullivan, K. L., Garg, I., Taylor, J. A., Claffey, K. P. Tags: Cell Cycle and Senescence Source Type: research
Synthetic Lethality in PTEN-Mutant Prostate Cancer Is Induced by Combinatorial PI3K/Akt and BCL-XL Inhibition
This study defines a synthetic lethal therapeutic combination with significant translational potential.
Overview: Synthetic lethality in PTEN-mutant prostate cancer cells with combined PI3K/Akt and BCL-XL inhibition. PTEN-mutant prostate cancer cells expressing ITGA5 bind to fibronectin in the putative bone marrow niche and transduce survival signals to BCL-XL. Additional PTEN-regulated signals independent of the PI3K/Akt pathway likely feed into the BCL-XL–regulated survival program to explain synthetic lethality observed with the combination.
Visual Overview: http://mcr.aacrjournals.org/content/early/2016/12/02/154...
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: Ren, W., Joshi, R., Mathew, P. Tags: Rapid Impact Source Type: research
A New Chromatin-Cytoskeleton Link in Cancer
The set domain containing 2 (SETD2) histone methyltransferase, located at 3p2, specifically trimethylates lysine 36 of histone H3 (H3K36me3). H3K36me3 is an active mark involved in transcriptional elongation and RNA processing and a key regulator of DNA repair. In fact, SETD2 is the only methyltransferase that "writes" the H3K36me3 mark. Recent results from Park and colleagues have found a new role for SETD2 in the methylation of K40 of α-tubulin. Loss of SETD2 abolishes methylation of K40 of α-tubulin and results in a dysfunctional mitotic spindle and abnormalities in cytokinesis. Thus, SETD2 links chromatin a...
Source: Molecular Cancer Research - November 30, 2016 Category: Cancer & Oncology Authors: Giaccia, A. J. Tags: Perspective Source Type: research
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
