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MTDH and FOXM1, Two Master Regulators in Gynecologic Cancer

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MTDH and FOXM1, Two Master Regulators in Gynecologic Cancer Central Medical Journal of Obstetrics and Gynecology Editorial *Corresponding author Xiangbing Meng, Department of Obstetrics and Gynecology, The University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, Iowa 52242, USA, MTDH and FOXM1, Two Master Tel: 3193358212; Fax: 3193358448; Email: xiangbing- [email protected] Regulators in Gynecologic Submitted: 31 August 2013 Accepted: 31 August 2013 Published: 02 September 2013 Cancer Copyright Shujie Yang1, Kimberly K Leslie1,2 and Xiangbing Meng1,2* © 2013 Yang et al. 1Departments of Obstetrics and Gynecology, The University of Iowa, USA OPEN ACCESS 2Holden Comprehension Cancer Center, The University of Iowa, USA Keywords • FOXM1 Abstract • MTDH/AEG-1/LYRIC Drug resistance and metastasis are the major challenges for treatment of • NPM gynecologic cancers. Tumor heterogeneity caused by diverse driver mutations in • ARF gynecologic cancers restricts the effective application targeted therapies. Both FOXM1 • DNA repair and MTDH are overexpressed and correlated with drug resistance and metastasis • Gynecologic cancers in various types of cancers including gynecologic cancers. Accumulated clinical and • Targeted therapy functional studies have demonstrated that elevated expression of both FOXM1 and MTDH is the consequence of diverse activating mutations in oncogenes such as PI3K, Ras, myc and loss of function mutations in tumor suppressor genes such as p53 and PTEN. We discuss FOXM1 and MTDH as potential prognostic markers and therapeutic targets in gynecologic cancers. ABBREVIATIONS especially when used in combination with chemotherapy, are promising and may allow us to tailor treatment to individual PARP: Poly-ADP-Ribose Polymerase; VEGF: Vascular 2, ]. Currently, mammalian Endothelial Growth Factor; VEGFR: Vascular Endothelial Growth Factor Receptors; PDGF: Platelet-Derived Growth Factor; FGF: patient and tumor genetic profiles [ 3 Fibroblast Growth Factor; HNSCC: Head and Neck Squamous target of rapamycin (mTOR) inhibitors, poly-ADP-ribose Cell Carcinoma; ESCC: Esophageal Squamous Cell Carcinoma; polymerase (PARP) inhibitors, tyrosine-kinase inhibitors for FOXO: Forkhead box class O; XRCC1: X-ray Repair Cross- vascular endothelial growth factor (VEGF), vascular endothelial Complementing protein 1; BRCA2: Breast Cancer-Associated growth factor receptors (VEGFR), platelet-derived growth factor gene 2; HR: Homologous Recombination; NHEJ: Non-Homologous cancers(PDGF), fibroblast[4 growth factor (FGF), and components of the End Joining; GFP: Green Fluorescent Protein; CNV: Copy Number EGFR pathway are being tested in clinical trials for gynecologic Variations; DSB: Double Strand Break; BRIP1: BRCA1-associated ]. Identification of new molecule(s) that are key BACH1 helicase; LPS: Lipo Poly Saccharides; OS: Overall Survival; effectors of carcinogenesis and progression in many tumor types PFS: Progress Free Survival; HCC: HepatoCellular Carcinoma; thatand whichtwo such can molecules,be targeted FOXM1 therapeutically [ -9] and would MTDH be [10 a significant- ], meet EOC: Epithelial Ovarian Cancer; Alb/MTDH: A transgenic mouse theseadvancement criteria inand the can development serve as ofnovel new diagnostic treatments. markers We propose and 5 13 with hepatocyte-specific expression of AEG-1 by directing therapeutic targets. Accumulated clinical and functional studies promoter.the expression of human AEG-1 under an upstream enhancer have demonstrated involvement of both FOXM1 and MTDH in region fused to the 335-base-pair core region of mouse albumin cell proliferation, chemoresistance, angiogenesis, invasion, and INTRODUCTION metastasis in various types of human cancers. Therefore, FOXM1 Although survival rate in gynecologic cancers have andO verexpression MTDH have been of identified MTDH a asnd prognostic FOXM1 in markers. cancers improved somewhat in the last decades, there are still many Elevated FOXM1 expression has been reported in various types challenges including early diagnosis, prevention, drug resistance, metastasis and drug toxicity [1]. Tumor heterogeneity limits ovarianof malignancies tumors [including14 gynecologic cancers. Overexpression gynecologic cancers [2]. These complexities represent major mostof FOXM1 commonly has beenupregulated observed genes in 87%in human of high-grade solid tumors serous in effective application of a standard single treatment modality in ]. FOXM1 has been identified as one of the therapies. Newly emerging targeted molecular inhibitors, challenges and impediments to developing effective cancer several gene expression profiling studies. The forkhead box class O (FOXO) family is comprised of multifunctional transcription Cite this article: Yang S, Leslie KK, Meng X (2013) MTDH and FOXM1, Two Master Regulators in Gynecologic Cancer. Med J Obstet Gynecol 1(2): 1011. Yang et al. (2013) Email: [email protected] Central impactfactors in(FOXO1, cell cycle FOXO3a, arrest, FOXO4invasion, and migration, FOXO6) andinvolved resistance in fine- to MTDH expression group versus 63.6 months and >50 months therapytuning a [ broad repertoire of downstream target genes which in the low MTDH expression group (p<0.001). Thus, increased expression of MTDH predicts for poor response to cisplatin 15]. Inactivation and suppression of FOXO, in particular and shorter survival. Correlation of MTDH expression with FOXO1 and FOXO3a, have been implicated, ]. FOXOin tumorigenesis and FOXM1 Atlassurgical ovarian debulking cancer has data been set. confirmed In endometrial in a systemic cancer, reviewthe most of bindand cancer to the sameprogression. response However, elements Forkhead in target subfamilygenes. Target member gene 279 patients with stage 3 or 4 serous EOC in the Cancer Genome transcriptionFOXM1 functions activated as a classic by FOXM1 oncogene is usually [16 17 repressed by FOXO. Figure 1 common cancer of the female genital tract, overall 5-year survival rate is more than 80% if disease is diagnosed early. However, FOXM1 itself is a direct target repressed by FOXO ( ). a substantial percentage of patients will relapse and develop drugs,This repression including ischemotherapy released by the agents inhibition paclitaxel, of FOXO doxorubicin, proteins thismetastatic purpose. disease. MTDH A expression biomarker is to increased. identify high risk patients up via the PI3K-AKT-FOXO axis. Sensitivity to many anti-cancer front needs to be developed. We propose that MTDH may serve Molecular mechanisms of increased expression FOXM1 and MTDH in cancer FOXOcisplatin –FOXM1 and targeted axis [22 therapies- ]. lapatinib, gefitinib, imatinib, and tamoxifen, are determined through PI3K-AKT and downstream There are six mechanisms through which FOXM1 An inverse relationship26 between MTDH expression level expression is elevated in different types of cancers. These are: and OS (overall survival), PFS (progression free survival) and -29]. MTDH overexpressions (i) amplification of the FOXM1 gene locus. The FOXM1 locus is metastasis free survival has been observed in a large number located at chromosome 12p13, a region frequently amplified of studies in diverse cancers [27 breast adenocarcinomas [ , normal tissues and was strongly correlated with poor outcome in non-Hodgkin’s lymphoma (NHL), cervical carcinomas and andwas detectedmetastasis in morein more than than40% 1000of breast breast cancers cancer compared patients. to pathway [ ] direct interaction36 37] with(ii) Increased nucleophosmin protein [stability.] and FOXM1 stability in cancer cells is increased via the WntFigure signaling 1 MTDH expression in breast cancer [ ]. For the most lethal 38 39 Genomic amplification is one of the mechanisms for the increased [40 phosphorylation by Cdk4,6/cyclinD complexes ( ) 30 ] (iii) Increased transcription. Transcription of FOXM1 is gynecological cancer in Western countries, epithelial ovarian 41- activated through the action of transcription factors E2F, c-Myc, cancer (EOC), high MTDH expression was detected in 64.8% with peritoneal metastasis and 83.7% with lymph node metastasis and hypoxia-inducible factor-1 (HIF-1) [ 43]. (iv) Mutations in the tumor suppressor genes p53 and Rb. FOXM1is regulated [among, 157 patients with EOC, including 49 patients with lymph node metastasis and 128 patients with peritoneal dissemination by two major tumor suppressors Rb and p53. Transcription of FOXM1 is repressed by p53 via a direct interaction on the p53 in31 patients32]. For withthe moststage common II–IV tumors type of which ovarian were cancer, resistant ovarian to releases FOXM1 transcriptional repression in cancers [44- response element of the FoxM1 promoter. Inactivation of p53 cisplatinserous carcinoma, than in sensitive expression patients of MTDH [ - was]. Mediansignificantly PFS andhigher OS ]. Rb inhibits FOXM1-mediated downstream transcription 33 35 46 were 30.4 months and 35.28 months, respectively, in the high Activationby directly by interacting oncogenic with signaling FOXM1. pathways. Phosphorylation FOXM1 is activatedof Rb by PTEN PI3K Cyclin D1/Cdk4 disrupts the repression of FOXM1 by Rb [47] (v) (A) (B) Ha-ras AKT MTDH FOXM1 PI3K by oncogenic signaling pathways including PI3K/Akt, EGFR, Raf/ AKT ARF FOXO3a MEK/MAPK, and Hedgehog [48]. (vi) Reduced expression of Rb NPM myc NFκB andFOXM1 miR-200b, targeting have microRNAs been shown results to reduce in the FOXM1 reduction expression of FOXM1 at p53 FOXM1 thein cancer mRNA cells. or protein Five miRNAs, level [49 miR-370,- ]. miR-31, miR-34, miR-134 MTDH 53 Cell cycle : PLK1 ,CCNB1,survivin, Cdc25C ,myc
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