Publications by authors named "Eldad Zacksenhaus"

78 Publications

Single allele loss-of-function mutations select and sculpt conditional cooperative networks in breast cancer.

Nat Commun 2021 09 2;12(1):5238. Epub 2021 Sep 2.

Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada.

The most common events in breast cancer (BC) involve chromosome arm losses and gains. Here we describe identification of 1089 gene-centric common insertion sites (gCIS) from transposon-based screens in 8 mouse models of BC. Some gCIS are driver-specific, others driver non-specific, and still others associated with tumor histology. Processes affected by driver-specific and histology-specific mutations include well-known cancer pathways. Driver non-specific gCIS target the Mediator complex, Ca signaling, Cyclin D turnover, RNA-metabolism among other processes. Most gCIS show single allele disruption and many map to genomic regions showing high-frequency hemizygous loss in human BC. Two gCIS, Nf1 and Trps1, show synthetic haploinsufficient tumor suppressor activity. Many gCIS act on the same pathway responsible for tumor initiation, thereby selecting and sculpting just enough and just right signaling. These data highlight ~1000 genes with predicted conditional haploinsufficient tumor suppressor function and the potential to promote chromosome arm loss in BC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-25467-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413298PMC
September 2021

SMAD1 as a biomarker and potential therapeutic target in drug-resistant multiple myeloma.

Biomark Res 2021 Jun 16;9(1):48. Epub 2021 Jun 16.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.

Background: SMAD1, a central mediator in TGF-β signaling, is involved in a broad range of biological activities including cell growth, apoptosis, development and immune response, and is implicated in diverse type of malignancies. Whether SMAD1 plays an important role in multiple myeloma (MM) pathogenesis and can serve as a therapeutic target are largely unknown.

Methods: Myeloma cell lines and primary MM samples were used. Cell culture, cytotoxicity and apoptosis assay, siRNA transfection, Western blot, RT-PCR, Soft-agar colony formation, and migration assay, Chromatin immunoprecipitation (Chip), animal xenograft model studies and statistical analysis were applied in this study.

Results: We demonstrate that SMAD1 is highly expressed in myeloma cells of MM patients with advanced stages or relapsed disease, and is associated with significantly shorter progression-free and overall survivals. Mechanistically, we show that SMAD1 is required for TGFβ-mediated proliferation in MM via an ID1/p21/p27 pathway. TGF-β also enhanced TNFα-Induced protein 8 (TNFAIP8) expression and inhibited apoptosis through SMAD1-mediated induction of NF-κB1. Accordingly, depletion of SMAD1 led to downregulation of NF-κB1 and TNFAIP8, resulting in caspase-8-induced apoptosis. In turn, inhibition of NF-κB1 suppressed SMAD1 and ID1 expression uncovering an autoregulatory loop. Dorsomorphin (DM), a SMAD1 inhibitor, exerted a dose-dependent cytotoxic effect on drug-resistant MM cells with minimal cytotoxicity to normal hematopoietic cells, and further synergized with the proteasomal-inhibitor bortezomib to effectively kill drug-resistant MM cells in vitro and in a myeloma xenograft model.

Conclusions: This study identifies SMAD1 regulation of NF-κB1/TNFAIP8 and ID1-p21/p27 as critical axes of MM drug resistance and provides a potentially new therapeutic strategy to treat drug resistance MM through targeted inhibition of SMAD1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40364-021-00296-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207655PMC
June 2021

ERK activation via A1542/3 limonoids attenuates erythroleukemia through transcriptional stimulation of cholesterol biosynthesis genes.

BMC Cancer 2021 Jun 9;21(1):680. Epub 2021 Jun 9.

State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Province Science City, High Tech Zone, Baiyun District, Guiyang, 550014, Guizhou Province, People's Republic of China.

Background: Cholesterol plays vital roles in human physiology; abnormal levels have deleterious pathological consequences. In cancer, elevated or reduced expression of cholesterol biosynthesis is associated with good or poor prognosis, but the underlying mechanisms are largely unknown. The limonoid compounds A1542 and A1543 stimulate ERK/MAPK by direct binding, leading to leukemic cell death and suppression of leukemia in mouse models. In this study, we investigated the downstream consequences of these ERK/MAPK agonists in leukemic cells.

Methods: We employed RNAseq analysis combined with Q-RT-PCR, western blot and bioinformatics to identify and confirm genes whose expression was altered by A1542 and A1543 in leukemic cells. ShRNA lentiviruses were used to silence gene expression. Cell culture and an animal model (BALB/c) of erythroleukemia induced by Friend virus were utilized to validate effects of cholesterol on leukemia progression.

Results: RNAseq analysis of A1542-treated cells revealed the induction of all 18 genes implicated in cholesterol biosynthesis. Expression of these cholesterol genes was blocked by cedrelone, an ERK inhibitor. The cholesterol inhibitor lovastatin diminished ERK/MAPK activation by A1542, thereby reducing leukemic cell death induced by this ERK1/2 agonist. Growth inhibition by cholesterol was observed both at the intracellular level, and when orally administrated into a leukemic mouse model. Both HDL and LDL also suppressed leukemogenesis, implicating these lipids as important prognostic markers for leukemia progression. Mechanistically, knockdown experiments revealed that the activation of SREBP1/2 by A1542-A1543 was responsible for induction of only a sub-set of cholesterol biosynthesis genes. Induction of other regulatory factors by A1542-A1543 including EGR1, AP1 (FOS + JUN) LDLR, IER2 and others may cooperate with SREBP1/2 to induce cholesterol genes. Indeed, pharmacological inhibition of AP1 significantly inhibited cholesterol gene expression induced by A1542. In addition to leukemia, high expression of cholesterol biosynthesis genes was found to correlate with better prognosis in renal cancer.

Conclusions: This study demonstrates that ERK1/2 agonists suppress leukemia and possibly other types of cancer through transcriptional stimulation of cholesterol biosynthesis genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-021-08402-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191108PMC
June 2021

Inhibition of eEF2K synergizes with glutaminase inhibitors or 4EBP1 depletion to suppress growth of triple-negative breast cancer cells.

Sci Rep 2021 04 28;11(1):9181. Epub 2021 Apr 28.

Max Bell Research Centre, Toronto General Research Institute, University Health Network, 101 College Street, Suite 5R406, Toronto, ON, M5G 1L7, Canada.

The eukaryotic elongation factor-2 kinase, eEF2K, which restricts protein translation elongation, has been identified as a potential therapeutic target for diverse types of malignancies including triple negative breast cancer (TNBC). However, the contexts in which eEF2K inhibition is essential in TNBC and its consequences on the proteome are largely unknown. Here we show that genetic or pharmacological inhibition of eEF2K cooperated with glutamine (Gln) starvation, and synergized with glutaminase (GLS1) inhibitors to suppress growth of diverse TNBC cell lines. eEF2K inhibition also synergized with depletion of eukaryotic translation initiation factor 4E-binding protein 1 (eIF4EBP1; 4EBP1), a suppressor of eukaryotic protein translation initiation factor 4E (eIF4E), to induce c-MYC and Cyclin D1 expression, yet attenuate growth of TNBC cells. Proteomic analysis revealed that whereas eEF2K depletion alone uniquely induced Cyclin Dependent Kinase 1 (CDK1) and 6 (CDK6), combined depletion of eEF2K and 4EBP1 resulted in overlapping effects on the proteome, with the highest impact on the 'Collagen containing extracellular matrix' pathway (e.g. COL1A1), as well as the amino-acid transporter, SLC7A5/LAT1, suggesting a regulatory loop via mTORC1. In addition, combined depletion of eEF2K and 4EBP1 indirectly reduced the levels of IFN-dependent innate immune response-related factors. Thus, eEF2K inhibition triggers cell cycle arrest/death under unfavourable metabolic conditions such as Gln-starvation/GLS1 inhibition or 4EBP1 depletion, uncovering new therapeutic avenues for TNBC and underscoring a pressing need for clinically relevant eEF2K inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-88816-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080725PMC
April 2021

FLI1 Induces Megakaryopoiesis Gene Expression Through WAS/WIP-Dependent and Independent Mechanisms; Implications for Wiskott-Aldrich Syndrome.

Front Immunol 2021 26;12:607836. Epub 2021 Feb 26.

State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China.

Wiskott-Aldrich Syndrome, WAS/WAVE, is a rare, X-linked immune-deficiency disease caused by mutations in the gene, which together with its homolog, N-, regulates actin cytoskeleton remodeling and cell motility. WAS patients suffer from microthrombocytopenia, characterized by a diminished number and size of platelets, though the underlying mechanism is not fully understood. Here, we identified FLI1 as a direct transcriptional regulator of and its binding partner . Depletion of either or in human erythroleukemic cells accelerated cell proliferation, suggesting tumor suppressor function of both genes in leukemia. Depletion of also led to a significant reduction in the percentage of CD41 and CD61 positive cells, which mark committed megakaryocytes. RNAseq analysis revealed common changes in megakaryocytic gene expression following FLI1 or WASP knockdown. However, in contrast to FLI1, WASP depletion did not alter expression of late-stage platelet-inducing genes. N-WASP was not regulated by FLI1, yet its silencing also reduced the percentage of CD41+ and CD61+ megakaryocytes. Moreover, combined knockdown of WASP and N-WASP further suppressed megakaryocyte differentiation, indicating a major cooperation of these related genes in controlling megakaryocytic cell fate. However, unlike WASP/WIP, N-WASP loss suppressed leukemic cell proliferation. WASP, WIP and N-WASP depletion led to induction of FLI1 expression, mediated by GATA1, and this may mitigate the severity of platelet deficiency in WAS patients. Together, these results uncover a crucial role for FLI1 in megakaryocyte differentiation, implicating this transcription factor in regulating microthrombocytopenia associated with Wiskott-Aldrich syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.607836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953068PMC
July 2021

Progression to Metastasis of Solid Cancer.

Cancers (Basel) 2021 Feb 10;13(4). Epub 2021 Feb 10.

Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 0A4, Canada.

Metastatic dissemination of cancer cells, their colonization at distal sites, and ultimate disruption of tissue physiology are the root causes of most deaths from solid cancers, particularly in tumor types where the primary lesion can be easily dissected and discarded [...].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13040717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916396PMC
February 2021

Ubash3b promotes TPA-mediated suppression of leukemogenesis through accelerated downregulation of PKCδ protein.

Biochimie 2021 May 5;184:8-17. Epub 2021 Feb 5.

State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou, 550014, PR China. Electronic address:

Acquired drug-resistance, often involving downregulation or mutations in the target protein, is a major caveat in precision medicine. Understanding mechanisms of resistance to therapeutic drugs may unravel strategies to overcome or prevent them. We previously identified phorbol ester (PE) compounds such as TPA that induce Protein Kinase δ (PKCδ), thereby suppressing leukemogenesis. Here we identified erythroleukemia cell lines that resist PEs and showed that reduced PKCδ protein expression underlies drug resistance. Reduced level of PKCδ in resistant cell lines was due to its phosphorylation followed by protein degradation. Indeed, proteasome inhibition prevented PE-induced loss of PKCδ. Accordingly, a combination of TPA and the proteasome inhibitor ALLN significantly suppressed leukemia in a mouse model of leukemia. PKCδ downregulation by TPA was independent of the downstream MAPK/ERK/P38/JNK pathway. Instead, expression of ubiquitin-associated and SH3 domain-containing protein b (Ubash3b) was induced by TPA, which leads to PKCδ protein dephosphorylation and degradation. This specific degradation was blocked by RNAi-mediated depletion of Ubash3b. In drug-sensitive leukemic cells, TPA did not induce Ubash3b, and consequently, PKCδ levels remained high. A PE-resistant cell line derived from PE-treated sensitive cells exhibited very low PKCδ expression. In these drug resistance cells, a Ubash3b independent mechanism led to PKCδ degradation. Thus, PE compounds in combination with proteasome or specific inhibitors for Ubash3b, or other factors can overcome resistance to TPA, leading to durable suppression of leukemic growth. These results identify Ubash3b as a potential target for drug development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biochi.2021.02.001DOI Listing
May 2021

Fer and FerT Govern Mitochondrial Susceptibility to Metformin and Hypoxic Stress in Colon and Lung Carcinoma Cells.

Cells 2021 01 7;10(1). Epub 2021 Jan 7.

The Mina and Everard Goodman Faculty of Life-Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel.

Aerobic glycolysis is an important metabolic adaptation of cancer cells. However, there is growing evidence that reprogrammed mitochondria also play an important metabolic role in metastatic dissemination. Two constituents of the reprogrammed mitochondria of cancer cells are the intracellular tyrosine kinase Fer and its cancer- and sperm-specific variant, FerT. Here, we show that Fer and FerT control mitochondrial susceptibility to therapeutic and hypoxic stress in metastatic colon (SW620) and non-small cell lung cancer (NSCLC-H1299) cells. Fer- and FerT-deficient SW620 and H1299 cells (SW∆Fer/FerT and H∆Fer/FerT cells, respectively) become highly sensitive to metformin treatment and to hypoxia under glucose-restrictive conditions. Metformin impaired mitochondrial functioning that was accompanied by ATP deficiency and robust death in SW∆Fer/FerT and H∆Fer/FerT cells compared to the parental SW620 and H1299 cells. Notably, selective knockout of the gene without affecting FerT expression reduced sensitivity to metformin and hypoxia seen in SW∆Fer/FerT cells. Thus, Fer and FerT modulate the mitochondrial susceptibility of metastatic cancer cells to hypoxia and metformin. Targeting Fer/FerT may therefore provide a novel anticancer treatment by efficient, selective, and more versatile disruption of mitochondrial function in malignant cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells10010097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826929PMC
January 2021

A C21-steroidal derivative suppresses T-cell lymphoma in mice by inhibiting SIRT3 via SAP18-SIN3.

Commun Biol 2020 12 3;3(1):732. Epub 2020 Dec 3.

State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China.

The SIN3 repressor complex and the NAD-dependent deacetylase SIRT3 control cell growth, and development as well as malignant transformation. Even then, a little known about cross-talks between these two chromatin modifiers or whether their interaction explored therapeutically. Here we describe the identification of a C-steroidal derivative compound, 3-O-chloroacetyl-gagamine, A671, which potently suppresses the growth of mouse and human T-cell lymphoma and erythroleukemia in vitro and preclinical models. A671 exerts its anti-neoplastic effects by direct interaction with Histone deacetylase complex subunit SAP18, a component of the SIN3 suppressor complex. This interaction stabilizes and activates SAP18, leading to transcriptional suppression of SIRT3, consequently to inhibition of proliferation and cell death. The resistance of cancer cells to A671 correlated with diminished SAP18 activation and sustained SIRT3 expression. These results uncover the SAP18-SIN3-SIRT3 axis that can be pharmacologically targeted by a C-steroidal agent to suppress T-cell lymphoma and other malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-020-01458-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713351PMC
December 2020

Methylation data of mouse Rb-deficient pineoblastoma.

Data Brief 2020 Oct 25;32:106229. Epub 2020 Aug 25.

Toronto General Research Institute - University Health Network, 67 College Street, Toronto, ON M5G 2M1, Canada.

Methylation profiling is widely used to study tumor biology and perform cluster analysis, particularly in brain cancer research where tissue biopsies are scarce. We have recently reported on the development of novel mouse models for germ line mutations in pineoblastoma (, 2020). Here, we present unpublished methylation profiling of 8 Rb-deleted/p53-deleted pineoblastoma from our mouse model as well as 3 normal cerebellum tissues as control. The primary dataset can be accessed via SRA (PRJNA638504). These methylation data can be used to perform inter- and intra-species comparisons with other brain cancers as well as with specific subtypes of pineoblastoma, and to investigate potential epigenetic mechanisms and pathways underlying Rb-deficient pineoblastoma-genesis..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dib.2020.106229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476231PMC
October 2020

Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy.

Nat Commun 2020 04 14;11(1):1825. Epub 2020 Apr 14.

Toronto General Research Institute, University Health Network, 67 College Street, Toronto, ON, M5G 2M1, Canada.

Pineoblastoma is a rare pediatric cancer induced by germline mutations in the tumor suppressors RB1 or DICER1. Presence of leptomeningeal metastases is indicative of poor prognosis. Here we report that inactivation of Rb plus p53 via a WAP-Cre transgene, commonly used to target the mammary gland during pregnancy, induces metastatic pineoblastoma resembling the human disease with 100% penetrance. A stabilizing mutation rather than deletion of p53 accelerates metastatic dissemination. Deletion of Dicer1 plus p53 via WAP-Cre also predisposes to pineoblastoma, albeit with lower penetrance. In silico analysis predicts tricyclic antidepressants such as nortriptyline as potential therapeutics for both pineoblastoma models. Nortriptyline disrupts the lysosome, leading to accumulation of non-functional autophagosome, cathepsin B release and pineoblastoma cell death. Nortriptyline further synergizes with the antineoplastic drug gemcitabine to effectively suppress pineoblastoma in our preclinical models, offering new modality for this lethal childhood malignancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-15585-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156401PMC
April 2020

MARCKS inhibition cooperates with autophagy antagonists to potentiate the effect of standard therapy against drug-resistant multiple myeloma.

Cancer Lett 2020 06 24;480:29-38. Epub 2020 Mar 24.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada. Electronic address:

Overexpression of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) is implicated in drug resistance and progression of multiple myeloma (MM). The basis for MARCKS induction and impact on MM are not known. Here we show that microRNA-34a (miR-34a), regulates MARCKS translation and is under-expressed in drug-resistant MM cells, leading to increased MARCKS protein level. Over-expression of miR-34a reduces MARCKS expression and sensitizes resistant cells to anti-myeloma drugs. A MARCKS peptide inhibitor (MPS) exerts a dose dependent cytotoxic effect on drug-resistant MM cells with minimal cytotoxicity to normal hematopoietic cells. MPS synergizes with the proteasomal-inhibitor bortezomib to effectively kill drug-resistant MM cells both in vitro and in a xenograft model of MM. While MARCKS inhibition killed MM cells, it also enhanced a pro-survival autophagic pathway that sustained growth following MARCKS inhibition. In accordance, combined treatment with MARCKS antagonists, bortezomib and the autophagy inhibitor, chloroquine, significantly diminished tumor growth in drug-resistant MM cell lines as well as primary MM cells. This study uncovers a mechanism of drug resistance involving miR-34a-MARCKS autoregulatory loop and provides a framework for a potentially new therapeutic strategy to overcome drug resistance in multiple myeloma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2020.03.020DOI Listing
June 2020

Erythropoietin Signaling in the Microenvironment of Tumors and Healthy Tissues.

Adv Exp Med Biol 2020 ;1223:17-30

State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou, China.

Erythropoietin (EPO), the primary cytokine of erythropoiesis, stimulates both proliferation and differentiation of erythroid progenitors and their maturation to red blood cells. Basal EPO levels maintain the optimum levels of circulating red blood cells. However, during hypoxia, EPO secretion and its expression is elevated drastically in renal interstitial fibroblasts, thereby increasing the number of erythroid progenitors and accelerating their differentiation to mature erythrocytes. A tight regulation of this pathway is therefore of paramount importance. The biological response to EPO is commenced through the involvement of its cognate receptor, EPOR. The receptor-ligand complex results in homodimerization and conformational changes, which trigger downstream signaling events and cause activation or inactivation of critical transcription factors that promote erythroid expansion. In recent years, recombinant human EPO (rEPO) has been widely used as a therapeutic tool to treat a number of anemias induced by infection, and chemotherapy for various cancers. However, several studies have uncovered a tumor promoting ability of EPO in man, which likely occurs through EPOR or alternative receptor(s). On the other hand, some studies have demonstrated a strong anticancer activity of EPO, although the mechanism still remains unclear. A thorough investigation of EPOR signaling could yield enhanced understanding of the pathobiology for a variety of disorders, as well as the potential novel therapeutic strategies. In this chapter, in addition to the clinical relevance of EPO/EPOR signaling, we review its anticancer efficacy within various tumor microenvironments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-3-030-35582-1_2DOI Listing
February 2020

FLI1 promotes protein translation via the transcriptional regulation of MKNK1 expression.

Int J Oncol 2020 Feb 16;56(2):430-438. Epub 2019 Dec 16.

State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Province Science City, High Tech Zone, Baiyun, Guiyang, Guizhou 550014, P.R. China.

The disruption of protein translation machinery is a common feature of cancer initiation and progression, and drugs that target protein translation offer new avenues for therapy. The translation initiation factor, eukaryotic initiation factor 4E (eIF4E), is induced in a number of cancer cell lines and is one such candidate for therapeutic intervention. Friend leukemia integration 1 (FLI1) is a potent oncogenic transcription factor that promotes various types of cancer by promoting several hallmarks of cancer progression. FLI1 has recently been implicated in protein translation through yet unknown mechanisms. This study identified a positive association between FLI1 expression and mitogen‑activated protein kinase (MAPK)‑interacting serine/threonine kinase1 (MKNK1), the immediate upstream regulator of the eIF4E initiation factor. The short hairpin RNA (shRNA)‑mediated silencing or overexpression of FLI1 in leukemic cell lines downregulated or upregulated MKNK1 expression, respectively. Promoter analysis identified a potent FLI1 binding site in the regulatory region of the MKNK1 promoter. In transient transfection experiments, FLI1 increased MKNK1 promoter activity, which was blocked by mutating the FLI1 binding site. FLI1 specifically affected the expression of MKNK1, but not that of MKNK2. The siRNA‑mediated downregulation of MKNK1 downregulated the expression of survivin (BIRC5) and significantly suppressed cell proliferation in culture. FLI1 inhibitory compounds were shown to downregulate this oncogene through the suppression of MAPK/extracellular‑regulated kinase (ERK) signaling and the subsequent activation of miR‑145, leading to a lower MKNK1 expression and the suppression of leukemic growth. These results uncover a critical role for FLI1 in the control of protein translation and the importance of targeting its function and downstream mediators, such as MKNK1, for cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/ijo.2019.4943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959374PMC
February 2020

Molecular stratification within triple-negative breast cancer subtypes.

Sci Rep 2019 12 13;9(1):19107. Epub 2019 Dec 13.

Toronto General Research Institute, University Health Network, 67 College Street, Toronto, Ontario, M5G 2M1, Canada.

Triple-negative breast cancer (TNBC) has been subdivided into six distinct subgroups: basal-like 1 (BL1), basal-like 2 (BL2), mesenchymal (M), mesenchymal stem-like (MSL), immunomodulatory (IM), and luminal androgen receptor (LAR). We recently identified a subgroup of TNBC with loss of the tumor suppressor PTEN and five specific microRNAs that exhibits exceedingly poor clinical outcome and contains TP53 mutation, RB1 loss and high MYC and WNT signalling. Here, show that these PTEN-low/miRNA-low lesions cluster with BL1 TNBC. These tumors exhibited high RhoA signalling and were significantly stratified on the basis of PTEN-low/RhoA-signalling-high with hazard ratios (HRs) of 8.2 (P = 0.0009) and 4.87 (P = 0.033) in training and test cohorts, respectively. For BL2 TNBC, we identified AKT1 copy gain/high mRNA expression as surrogate for poor prognosis (HR = 3.9; P = 0.02 and HR = 6.1; P = 0.0032). In IM, programmed cell death 1 (PD1) was elevated and predictive of poor prognosis (HR = 5.3; P = 0.01 and HR = 3.5; P < 0.004). Additional alterations, albeit without prognostic power, characterized each subtype including high E2F2 and TGFβ signalling and CXCL8 expression in BL2, high IFNα and IFNγ signalling and CTLA4 expression in IM, and high EGFR signalling in MSL, and may be targeted for therapy. This study identified PTEN-low/RhoA-signalling-high, and high AKT1 and PD1 expression as potent prognostications for BL1, BL2 and IM subtypes with survival differences of over 14, 2.75 and 10.5 years, respectively. This intrinsic heterogeneity could be exploited to prioritize patients for precision medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-55710-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911070PMC
December 2019

Opposing effects of NPM1wt and NPM1c mutants on AKT signaling in AML.

Leukemia 2020 04 14;34(4):1172-1176. Epub 2019 Nov 14.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-019-0621-7DOI Listing
April 2020

Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity.

BMC Cancer 2019 Aug 2;19(1):764. Epub 2019 Aug 2.

Department of Immunology State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550025, China.

Background: MAPK/ERK kinases transmit signals from many growth factors/kinase receptors during normal cell growth/differentiation, and their dysregulation is a hallmark of diverse types of cancers. A plethora of drugs were developed to block this kinase pathway for clinical application. With the exception of a recently identified agent, EQW, most of these inhibitors target upstream factors but not ERK1/2; no activator of ERK1/2 is currently available.

Method: A library of compounds isolated from medicinal plants of China was screened for anti-cancer activities. Three limonoid compounds, termed A1541-43, originally isolated from the plant Melia azedarach, exhibiting strong anti-leukemic activity. The anti-neoplastic activity and the biological target of these compounds were explored using various methods, including western blotting, flow cytometry, molecular docking and animal model for leukemia.

Results: Compounds A1541-43, exhibiting potent anti-leukemic activity, was shown to induce ERK1/2 phosphorylation. In contrast, the natural product Cedrelone, which shares structural similarities with A1541-43, functions as a potent inhibitor of ERK1/2. We provided evidence that A1541-43 and Cedrelone specifically target ERK1/2, but not the upstream MAPK/ERK pathway. Computational docking analysis predicts that compounds A1541-43 bind a region in ERK1/2 that is distinct from that to which Cedrelone and EQW bind. Interestingly, both A1541-43, which act as ERK1/2 agonists, and Cedrelone, which inhibit these kinases, exerted strong anti-proliferative activity against multiple leukemic cell lines, and induced robust apoptosis as well as erythroid and megakaryocytic differentiation in erythroleukemic cell lines. These compounds also suppressed tumor progression in a mouse model of erythroleukemia.

Conclusions: This study identifies for the first time activators of ERK1/2 with therapeutic potential for the treatment of cancers driven by dysregulation of the MAPK/ERK pathway and possibly for other disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-019-5914-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679490PMC
August 2019

Identification of diterpenoid compounds that interfere with Fli-1 DNA binding to suppress leukemogenesis.

Cell Death Dis 2019 02 11;10(2):117. Epub 2019 Feb 11.

State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550025, China.

The ETS transcription factor Fli-1 controls the expression of genes involved in hematopoiesis including cell proliferation, survival, and differentiation. Dysregulation of Fli-1 induces hematopoietic and solid tumors, rendering it an important target for therapeutic intervention. Through high content screens of a library of chemicals isolated from medicinal plants in China for inhibitors of a Fli-1 transcriptional reporter cells, we hereby report the identification of diterpenoid-like compounds that strongly inhibit Fli-1 transcriptional activity. These agents suppressed the growth of erythroleukemic cells by inducing apoptosis and differentiation. They also inhibited survival and proliferation of B-cell leukemic cell lines as well as primary B-cell lymphocytic leukemia (B-CLL) isolated from 7 patients. Moreover, these inhibitors blocked leukemogenesis in a mouse model of erythroleukemia, in which Fli-1 is the driver of tumor initiation. Computational docking analysis revealed that the diterpenoid-like compounds bind with high affinity to nucleotide residues in a pocket near the major groove within the DNA-binding sites of Fli-1. Functional inhibition of Fli-1 by these compounds triggered its further downregulation through miR-145, whose promoter is normally repressed by Fli-1. These results uncover the importance of Fli-1 in leukemogenesis, a Fli-1-miR145 autoregulatory loop and new anti-Fli-1 diterpenoid agents for the treatment of diverse hematological malignancies overexpressing this transcription factor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-019-1363-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370842PMC
February 2019

A subgroup of microRNAs defines PTEN-deficient, triple-negative breast cancer patients with poorest prognosis and alterations in RB1, MYC, and Wnt signaling.

Breast Cancer Res 2019 01 31;21(1):18. Epub 2019 Jan 31.

Toronto General Research Institute - University Health Network, 67 College Street, Rm. 407, Toronto, Ontario, M5G 2M1, Canada.

Background: Triple-negative breast cancer (TNBC) represents a heterogeneous group of ER- and HER2-negative tumors with poor clinical outcome. We recently reported that Pten-loss cooperates with low expression of microRNA-145 to induce aggressive TNBC-like lesions in mice. To systematically identify microRNAs that cooperate with PTEN-loss to induce aggressive human BC, we screened for miRNAs whose expression correlated with PTEN mRNA levels and determined the prognostic power of each PTEN-miRNA pair alone and in combination with other miRs.

Methods: Publically available data sets with mRNA, microRNA, genomics, and clinical outcome were interrogated to identify miRs that correlate with PTEN expression and predict poor clinical outcome. Alterations in genomic landscape and signaling pathways were identified in most aggressive TNBC subgroups. Connectivity mapping was used to predict response to therapy.

Results: In TNBC, PTEN loss cooperated with reduced expression of hsa-miR-4324, hsa-miR-125b, hsa-miR-381, hsa-miR-145, and has-miR136, all previously implicated in metastasis, to predict poor prognosis. A subgroup of TNBC patients with PTEN-low and reduced expression of four or five of these miRs exhibited the worst clinical outcome relative to other TNBCs (hazard ratio (HR) = 3.91; P < 0.0001), and this was validated on an independent cohort (HR = 4.42; P = 0.0003). The PTEN-low/miR-low subgroup showed distinct oncogenic alterations as well as TP53 mutation, high RB1-loss signature and high MYC, PI3K, and β-catenin signaling. This lethal subgroup almost completely overlapped with TNBC patients selected on the basis of Pten-low and RB1 signature loss or β-catenin signaling-high. Connectivity mapping predicted response to inhibitors of the PI3K pathway.

Conclusions: This analysis identified microRNAs that define a subclass of highly lethal TNBCs that should be prioritized for aggressive therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13058-019-1098-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357448PMC
January 2019

Novel racemosin B derivatives as new therapeutic agents for aggressive breast cancer.

Bioorg Med Chem 2018 12 16;26(23-24):6096-6104. Epub 2018 Nov 16.

State Key Laboratory for Functions and Applications of Medicinal Plants/College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang 550014, PR China. Electronic address:

Carbazole derivatives show anti-cancer activity and are of great interest for drug development. In this study, we synthesized and analyzed several new alkylamide derivatives of racemocin B, a natural indolo[3,2-a]carbazole molecule originally isolated from the green alga Caulerpa racemose. Several alkylamide derivatives were found to exhibit moderate to strong growth inhibition against human breast cancer cell lines. They induced G2/M cell cycle arrest and apoptosis in the aggressive triple-negative breast cancer cell line MDA-MB-231. Among these derivatives, compound 25 with the lowest IC induced cell death by suppressing autophagy. This was accompanied by inhibition of autophagic flux and accumulation of autophagy protein 1 light chain 3, LC3II, and p62. The novel alkylamide derivative offers a potential new treatment for human breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2018.11.014DOI Listing
December 2018

Novel flavagline-like compounds with potent Fli-1 inhibitory activity suppress diverse types of leukemia.

FEBS J 2018 12 20;285(24):4631-4645. Epub 2018 Nov 20.

State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China.

E26 transformation-specific (ETS) gene family contains a common DNA-binding domain, the ETS domain, responsible for sequence-specific DNA recognition on target promoters. The Fli-1 oncogene, a member of ETS gene family, plays a critical role in hematopoiesis and is overexpressed in diverse hematological malignancies. This ETS transcription factor regulates genes controlling several hallmarks of cancer and thus represents an excellent target for cancer therapy. By screening compounds isolated from the medicinal plant Dysoxylum binectariferum in China, we identified two chemically related flavagline-like compounds including 4'-demethoxy-3',4'-methylenedioxyrocaglaol and rocaglaol that strongly inhibited Fli-1 transactivation ability. These compounds altered expression of Fli-1 target genes including GATA1, EKLF, SHIP1, and BCL2. Consequently, the flavagline-like compounds suppressed proliferation, induced apoptosis, and promoted erythroid differentiation of leukemic cells in culture. These compounds also suppressed erythroleukemogenesis in vivo in a Fli-1-driven mouse model. Mechanistically, the compounds blocked c-Raf-MEK-MAPK/ERK signaling, reduced phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), and inhibited Fli-1 protein synthesis. Consistent with its high expression in myelomas, B-cell lymphoma, and B chronic lymphocytic leukemia (B-CLL), pharmacological inhibition of Fli-1 by the flavagline-like compounds or genetic knock-down via shRNA significantly hindered proliferation of corresponding cell lines and patients' samples. These results uncover a critical role of Fli-1 in growth and survival of various hematological malignancies and point to flavagline-like agents as lead compounds for the development of anti-Fli-1 drugs to treat leukemias/lymphomas overexpressing Fli-1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/febs.14690DOI Listing
December 2018

Cdh1 and Pik3ca Mutations Cooperate to Induce Immune-Related Invasive Lobular Carcinoma of the Breast.

Cell Rep 2018 10;25(3):702-714.e6

Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. Electronic address:

CDH1 and PIK3CA are the two most frequently mutated genes in invasive lobular carcinoma (ILC) of the breast. Transcription profiling has identified molecular subtypes for ILC, one of which, immune-related (IR), is associated with gene expression linked to lymphocyte and macrophage infiltration. Here, we report that deletion of Cdh1, together with activation of Pik3ca in mammary epithelium of genetically modified mice, leads to formation of IR-ILC-like tumors with immune cell infiltration, as well as gene expression linked to T-regulatory (Treg) cell signaling and activation of targetable immune checkpoint pathways. Interestingly, these tumors show enhanced Rac1- and Yap-dependent transcription and signaling, as well as sensitivity to PI3K, Rac1, and Yap inhibitors in culture. Finally, high-dimensional immunophenotyping in control mouse mammary gland and IR-ILC tumors by mass cytometry shows dramatic alterations in myeloid and lymphoid populations associated with immune suppression and exhaustion, highlighting the potential for therapeutic intervention via immune checkpoint regulators.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2018.09.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276789PMC
October 2018

CDC25 as a common therapeutic target for triple-negative breast cancer - the challenges ahead.

Mol Cell Oncol 2018 15;5(4):e1481814. Epub 2018 Aug 15.

Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada.

The dual phosphatase CDC25 has recently been identified as a target for diverse triple-negative breast cancers including -deficient tumors. Moreover, CDC25 inhibitors effectively synergize with PI3K inhibitors to suppress tumor growth. We discuss these findings and the challenges that lie ahead in bringing CDC25 inhibitors to the clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/23723556.2018.1481814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6149702PMC
August 2018

The vulnerability of RB loss in breast cancer: Targeting a void in cell cycle control.

Oncotarget 2018 Jul 24;9(57):30940-30941. Epub 2018 Jul 24.

Erik S. Knudsen: Department of Molecular and Cellular Biology, Roswell Park Cancer Center, Buffalo, New York, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.25797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089558PMC
July 2018

Associations Between XPD Lys751Gln Polymorphism and Leukemia: A Meta-Analysis.

Front Genet 2018 14;9:218. Epub 2018 Jun 14.

State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China.

The aim of the present study was to define the potential relationship between xeroderma pigmentosum group D (XPD) Lys751Gln polymorphisms and the risk of leukemia. A comprehensive search of Pubmed, Web of Science, EBSCO, the Cochrane Library and China National Knowledge Infrastructure was conducted to identify original articles published before March 2017 concerning the association between XPD Lys751Gln polymorphisms and leukemia risk. A literature quality assessment was performed using the Newcastle-Ottawa Scale. Heterogeneity across studies was assessed using statistics. Random- or fixed-effects models were used to calculate pooled odds ratios (ORs) in the presence or absence of heterogeneity, respectively. Sensitivity analysis was used to assess the influence of individual studies on the pooled estimate. Publication bias was investigated using funnel plots and Egger's regression test. All data analyses were performed using Stata 14.0 and Revman 5.3. Fourteen studies with a total of 7525 participants (2,757 patients; 4,768 controls) were included in this meta-analysis. We found that XPD Lys751Gln polymorphisms significantly increased the risk of developing leukemia in both dominant OR = 1.21, 95%CI [1.10-1.35], ≤ 0.001) and heterozygote (OR = 1.22, 95%CI [1.09-1.36], ≤ 0.001) model. An allele model showed a borderline significant increase in leukemia risk (OR = 1.13, 95%CI [1.00-1.27], = 0.05). A subgroup analysis revealed a consistent association between XPD Lys751Gln polymorphisms and leukemia risk for some genetic models in Caucasian populations, adult or chronic groups, and in almost all models of childhood or acute groups. Our results indicate that XPD Lys751Gln polymorphism increases the risk of leukemia, especially in childhood and acute cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2018.00218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073102PMC
June 2018

Identification of CDC25 as a Common Therapeutic Target for Triple-Negative Breast Cancer.

Cell Rep 2018 04;23(1):112-126

Toronto General Research Institute - University Health Network, 67 College Street, Toronto, ON, Canada M5G 2M1; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada. Electronic address:

CDK4/6 inhibitors are effective against cancer cells expressing the tumor suppressor RB1, but not RB1-deficient cells, posing the challenge of how to target RB1 loss. In triple-negative breast cancer (TNBC), RB1 and PTEN are frequently inactivated together with TP53. We performed kinome/phosphatase inhibitor screens on primary mouse Rb/p53-, Pten/p53-, and human RB1/PTEN/TP53-deficient TNBC cell lines and identified CDC25 phosphatase as a common target. Pharmacological or genetic inhibition of CDC25 suppressed growth of RB1-deficient TNBC cells that are resistant to combined CDK4/6 plus CDK2 inhibition. Minimal cooperation was observed in vitro between CDC25 antagonists and CDK1, CDK2, or CDK4/6 inhibitors, but strong synergy with WEE1 inhibition was apparent. In accordance with increased PI3K signaling following long-term CDC25 inhibition, CDC25 and PI3K inhibitors effectively synergized to suppress TNBC growth both in vitro and in xenotransplantation models. These results provide a rationale for the development of CDC25-based therapies for diverse RB1/PTEN/TP53-deficient and -proficient TNBCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2018.03.039DOI Listing
April 2018

Mitochondrial OXPHOS Induced by RB1 Deficiency in Breast Cancer: Implications for Anabolic Metabolism, Stemness, and Metastasis.

Trends Cancer 2017 11 17;3(11):768-779. Epub 2017 Oct 17.

Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, 67 College Street, Toronto, ONT M5G 2M1, Canada.

A switch from catabolic to anabolic metabolism, a major hallmark of cancer, enables rapid cell duplication, and is driven by multiple oncogenic alterations, including PIK3CA mutation, MYC amplification, and TP53 loss. However, tumor growth requires active mitochondrial function and oxidative phosphorylation (OXPHOS). Recently, loss of the retinoblastoma (RB1) tumor suppressor in breast cancer was shown to induce mitochondrial protein translation (MPT) and OXPHOS. Here, we discuss how increased OXPHOS can enhance anabolic metabolism and cell proliferation, as well as cancer stemness and metastasis. Mitochondrial STAT3, FER/FER-T, and CHCHD2 are also implicated in OXPHOS. We propose that RB1 loss represents a prototypic oncogenic alteration that promotes OXPHOS, that aggressive tumors acquire lethal combinations of oncogenes and tumor suppressors that stimulate anabolism versus OXPHOS, and that targeting both metabolic pathways would be therapeutic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.trecan.2017.09.002DOI Listing
November 2017

microRNA-143/145 loss induces Ras signaling to promote aggressive Pten-deficient basal-like breast cancer.

JCI Insight 2017 Aug 3;2(15). Epub 2017 Aug 3.

Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada.

The tumor suppressor PTEN is frequently inactivated in breast and other cancers; yet, germ-line mutations in this gene induce nonmalignant hamartomas, indicating dependency on additional cooperating events. Here we show that most tumors derived from conditional deletion of mouse pten in mammary epithelium are highly differentiated and lack transplantable tumor-initiating cells (TICs) capable of seeding new tumors following orthotopic injection of FACS-sorted or tumorsphere cells. A rare group of poorly differentiated tumors did harbor transplantable TICs. These transplantable tumors exhibited distinct molecular classification, signaling pathways, chromosomal aberrations, and mutational landscape, as well as reduced expression of microRNA-143/145 (miR-143/145). Stable knockdown of miR-143/145 conferred tumorigenic potential upon poorly transplantable pten-deficient tumor cells through a mechanism involving induction of RAS signaling, leading to increased sensitivity to MEK inhibition. In humans, miR-145 deficiency significantly correlated with elevated RAS-pathway activity in basal-like breast cancer, and patients with combined PTEN/miR-145 loss or PTEN-loss/high RAS-pathway activity exhibited poor clinical outcome. These results underscore a selective pressure for combined PTEN loss together with RAS-pathway activation, either through miR-145 loss or other mechanisms, in basal-like breast cancer, and a need to identify and prioritize these tumors for aggressive therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.93313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543917PMC
August 2017

Identification of cell proliferation, immune response and cell migration as critical pathways in a prognostic signature for HER2+:ERα- breast cancer.

PLoS One 2017 20;12(6):e0179223. Epub 2017 Jun 20.

Division of Advanced Diagnostics, Toronto General Research Institute-University Health Network, Toronto, Ontario, Canada.

Background: Multi-gene prognostic signatures derived from primary tumor biopsies can guide clinicians in designing an appropriate course of treatment. Identifying genes and pathways most essential to a signature performance may facilitate clinical application, provide insights into cancer progression, and uncover potentially new therapeutic targets. We previously developed a 17-gene prognostic signature (HTICS) for HER2+:ERα- breast cancer patients, using genes that are differentially expressed in tumor initiating cells (TICs) versus non-TICs from MMTV-Her2/neu mammary tumors. Here we probed the pathways and genes that underlie the prognostic power of HTICS.

Methods: We used Leave-One Out, Data Combination Test, Gene Set Enrichment Analysis (GSEA), Correlation and Substitution analyses together with Receiver Operating Characteristic (ROC) and Kaplan-Meier survival analysis to identify critical biological pathways within HTICS. Publically available cohorts with gene expression and clinical outcome were used to assess prognosis. NanoString technology was used to detect gene expression in formalin-fixed paraffin embedded (FFPE) tissues.

Results: We show that three major biological pathways: cell proliferation, immune response, and cell migration, drive the prognostic power of HTICS, which is further tuned by Homeostatic and Glycan metabolic signalling. A 6-gene minimal Core that retained a significant prognostic power, albeit less than HTICS, also comprised the proliferation/immune/migration pathways. Finally, we developed NanoString probes that could detect expression of HTICS genes and their substitutions in FFPE samples.

Conclusion: Our results demonstrate that the prognostic power of a signature is driven by the biological processes it monitors, identify cell proliferation, immune response and cell migration as critical pathways for HER2+:ERα- cancer progression, and defines substitutes and Core genes that should facilitate clinical application of HTICS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179223PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478114PMC
September 2017
-->