In addition, Eph molecules operate in the tumor microenvironment, such as in vascular endothelial cells, influencing the ability of that family RTKs to promote carcinoma progression and metastasis. Studies of tumor-cell-autonomous effects of Eph receptors demonstrate their dual roles in tumor suppression and tumor promotion. The complex nature of Eph receptor signaling and crosstalk with other RTKs presents a different challenge and an opportunity to develop therapeutic intervention strategies for targeting breast cancer. Eph receptor tyrosine kinase (RTK) signaling regulates cancer initiation and metastatic progression through multiple mechanisms.
Original post by David Vaught, Dana M Brantley-Sieders and Jin Chen
The PcG-target genes INK4A and ARF are not expressed in tumors with high BMI1, but they are expressed in tumors with EZH2 overexpression. Based on their role in stem cells, EZH2 and BMI1 have been predicted to contribute to a poor outcome for cancer patients.
Whilst that may reflect transformation of different cell types, we plus observed a functional difference. Conclusions:
Overall, our notes highlight that whereas EZH2 and BMI1 may operate in a ‘linear’ pathway in normal development, their overexpression has different functional consequences for breast tumorigenesis. ARF expression results in TP53 activation, and we find a significantly higher proportion of TP53 mutations in tumors with high EZH2. IntroductionPolycombGroup (PcG) proteins maintain gene repression through histone modifications and have been implicated in stem cell regulation and cancer. EZH2 is part of Polycomb Repressive Complex 2 (PRC2) and trimethylates H3K27. that histone mark recruits […]
Original post by Alexandra M Pietersen, Hugo M Horlings, Michael Hauptmann, Anita Langerod, Abderrahim Ajouaou, Paulien Cornelissen-Steijger, Lodewijk F Wessels, Jos Jonkers, Marc J van de Vijver and Maarten van Lohuizen
To search for SNPs affecting tumour biology, cases were stratified into subgroups according to oestrogen receptor (ER) status and grade and tested for organization.
Stratifying POSH cases by tumour characteristics identified SNPs in FGFR2 and TOX3 that are associated with ER positive disease and SNPs in ATM associated with ER negative disease.
Here, we determine how these variants influence breast cancer prognosis, risk, and tumour characteristics.
For MMP7, TOX3, and MAP3K1, the effects on survival are independent of the main recognised clinical prognostic factors. These findings need to be validated by further studies in similar patient groups. Analysis of prognosis identified eight SNPs in six genes (MAP3K1, DAPK1, LSP1, MMP7, TOX3, and ESR1) and one region without genes on 8q24 that are associated with survival. The SNP in 8q24 is more weakly associated with independent effects on survival. To identify SNPs that alter the […]
Original post by William Tapper, Victoria Hammond, Susan Gerty, Sarah Ennis, Peter Simmonds, Andrew Collins, The POSH steering group and Diana Eccles
IntroductionDespite intense studies on the mechanisms of chemotherapeutic drug resistance in human breast cancer, few reports have systematically investigated mechanisms underlying resistance to the chemotherapy-sensitizing agent, tumor necrosis factor-alpha (TNF-alpha). We further demonstrate that MEK5-mediated progression to an EMT phenotype is dependent upon intact Erk5 and associated with upregulation of SNAI2 and ZEB1 expression.
Methods:
To compare differences in the proteome of the TNF-alpha resistant MCF-7 breast cancer cell line MCF-7-MEK5, mediated by MEK5/Erk5 signaling, and its parental TNF-alpha sensitive MCF-7 cell line MCF-7-VEC, two dimensional gel electrophoresis and high performance capillary liquid chromatography coupled to tandem mass spectrometry approaches were used.
Conclusions:
that study demonstrates that MEK5 overexpression promotes a TNF-alpha resistance phenotype associated with distinct proteomic changes (upregulation of VIM/vim, GSTP1/gstp1, and CKB/ckb; and downregulation of KRT8/krt8, KRT19/krt19 and GSTM3/gstm3). Results:
Proteomic analyses and PCR assays were used to identify and confirm differential expression of proteins. […]
Original post by Changhua Zhou, Ashley M Nitschke, Wei Xiong, Qiang Zhang, Yan Tang, Michael Bloch, Steven Elliott, Yun Zhu, Lindsey Bazzone, David Yu, Christopher B Weldon, Rachel Schiff, John A McLachlan, Barbara S Beckman, Thomas E Wiese, Kenneth P Nephew, Bin Shan, Matthew E Burow and Guangdi Wang
Results:
We found that DC increased the number of intestinal metastases generated from 4T1 cell tumors grafted into the fat pad. Here, we supply evidence for a novel mechanism by which DC reduces apoptosis that is induced by the sphingolipid ceramide in breast cancer cells.
DC plus increased the gene expression of the vascular endothelial growth factor (VEGF) receptor 2 (Flk-1), suggesting that DC enhanced the initial growth of secondary tumors adjacent to blood vessels. DC promoted survival of CD44(+) cells, which was concurrent with reduced levels of activated caspase 3 and ceramide, a sphingolipid inducing apoptosis in 4T1 cells. These cells were CD44(+), a marker that has been suggested to be expressed on breast cancer stem cells. Reducing the level or effect of serum DC and elevating ceramide in BCPCs by treatment with Z-guggulsterone and/or VEGFR2/Flk-1 antagonists may thus be a promising strategy […]
Original post by Kannan Krishnamurthy, Guanghu Wang, Dmitriy Rokhfeld and Erhard Bieberich
Methods:
We used a nationwide, population-based case-case design of 2640 Swedish women aged 50 to 74 years with postmenopausal breast cancer during 1993 to 1995, followed up to 31st December 2000. IntroductionHormonal factors are implicated in tumor progression and it is possible that factors influencing breast cancer induction could affect prognosis. Our study investigated the effects of menstrual risk factors on tumor characteristics and survival in postmenopausal breast cancer. Early menarche significantly increased the risk of lymph node metastases. Survival was poorest in women with the earliest age at menarche, with a 72% increased risk of dying within five years after diagnosis [hazard ratio (HR) = 1.72 (95% CI: 1.02 - 2.89)]. No significant associations were observed for other menstrual factors with tumor characteristics or survival. It remains to be established whether the associations are attributable to age at menarche […]
Original post by Chantal C Orgeas, Per Hall, Lena U Rosenberg and Kamila Czene
After performing an in vitro wound-healing assay, we observed that SNAI1-DN cells migrate more slowly than MDA-mock cells and in a more collective manner. Conclusions:
In the absence of functional SNAI1, the expression of PAI-1 transcripts is decreased while the protein is redistributed at the leading edge of migrating cells in a manner comparable to that seen in normal epithelial cells. The Plasminogen Activation system (PA system), including urokinase plasminogen activator (uPA), its receptor, and its inhibitor, plasminogen activator inhibitor type 1(PAI-1), additionally plays a key role in cancer invasion and metastasis, either through proteolytic degradation or by non proteolytic modulation of cell adhesion and migration. The blockade of SNAI1 activity resulted in the redistribution of PAI -1 in SNAI1-DN cells decorating large lamellipodia which were commonly found structures in these cells.
PAI-1 distribution was assessed by immunostaining.
In that study we aimed to determine […]
Original post by Elizabeth Fabre-Guillevin, Michel Malo, Amandine Cartier-Michaud, Hector Peinado, Gema Moreno-Bueno, Benoît Vallée, Daniel A Lawrence, José Palacios, Amparo Cano, Georgia Barlovatz-Meimon and Cécile Charrière-Bertrand
Results:
Using an in vitro kinase assay, RSK1 and RSK2 were shown to directly phosphorylate YB-1. Using Motifscan we identified p90 ribosomal S6 kinase (RSK) as a potential candidate for activating YB-1.
that implicates the EGFR/RSK/YB-1 pathway as an urgent component of BLBC providing an critical opportunity for therapeutic intervention. Methods:
Inhibition of RSK1 and RSK2 was achieved using siRNA and the small molecule SL0101. The RSK inhibitor SL0101 decreased the ability of YB-1 to bind the promoter, transactivate and ultimately reduced EGFR expression. The impact of inhibiting RSK on YB-1 operate was measured by luciferase assays and chromatin immunoprecipitation.
RSK1, RSK2, activated RSK and kinase-dead RSK were expressed in HCC1937 cells. Supporting that observation, RSK2-/- mouse embryo fibroblasts lose the ability to phosphorylate YB-1 in response to EGF. In immortalized breast epithelial cells […]
Original post by Anna L Stratford, Christopher J Fry, Curtis Desilets, Alastair H Davies, Yong Y Cho, Yvonne Li, Zigang Dong, Isabelle M Berquin, Philippe P Roux and Sandra E Dunn
Over the last eight years there has been a wealth of breast cancer gene expression studies, the majority of these have focused upon characterising a tumour at presentation, before treatment rather than looking at the effects of treatment on the tumour. More recently, a number of groups have moved from predicting prognosis based upon expanded term follow-up to alternative approaches of using expression profiling to measure the effect of treatment on breast tumours and the potential predict response to therapy using either post-treatment samples or both pre- and post- samples. Whilst that provides great potential to further our understanding of the mode of action of treatments and more accurately choose which patients will benefit from a specific treatment, serious issues of experimental design must be considered.
Original post by Andrew H Sims and John MS Bartlett
In the present study, we evaluated whether buthionine sulfoximine (BSO), a potent inhibitor of glutathione (GSH) synthesis, is capable of sensitizing antihormone resistant MCF-7:2A cells to estradiol-induced apoptosis. Results:
Exposure of MCF-7:2A cells to 1 nM E2 plus 100 microM BSO combination for 48 to 96 hours produced a 7-fold increase in apoptosis whereas the individual treatments had no significant effect on growth. Induction of apoptosis by the combination treatment of E2 plus BSO was evidenced by changes in Bcl-2 and Bax expression. The in vitro results of the MCF-7:2A cell line were further confirmed in vivo in a mouse xenograft model.
IntroductionEstrogen deprivation using aromatase inhibitors is one of the standard treatments for postmenopausal women with estrogen receptor (ER)-positive breast cancer, however, one of the consequences of prolonged estrogen suppression is acquired drug resistance. In contrast, we have another estrogen deprived cell […]
Original post by Joan S Lewis-Wambi, Helen R Kim, Chris Wambi, Roshani Patel, Jennifer R Pyle, Andres J Klein-Szanto and V Craig Jordan