Central Medical Journal of Obstetrics and Gynecology Cite this article: Yang S, Leslie KK, Meng X (2013) MTDH and FOXM1, Two Master Regulators in Gynecologic Cancer. Med J Obstet Gynecol 1(1): 1009. *Corresponding author Xia ng b ing Me ng , De p a rtme nt o f O b ste tric s a nd G yne c o lo g y, The Unive rsity o f Io wa Ho sp ita ls a nd C linic s, 200 Ha wkins Drive , Io wa C ity, Io wa 52242, USA, Te l: 3193358212; Fax: 3193358448; Email: xiangbing- meng@uiowa.edu Submitte d: 31 August 2013 Accepted: 31 August 2013 Publishe d: 02 Se p te m b e r 2013 Copyright © 2013 Ya ng e t a l. OPEN ACCESS Editorial MTDH and FOXM1, Two Master Regulators in Gynecologic Cancer Shujie Yang 1 , Kimberly K Leslie 1,2 and Xiangbing Meng 1,2 * 1 Departments of Obstetrics and Gynecology, The University of Iowa, USA 2 Holden Comprehension Cancer Center, The University of Iowa, USA ABBREVIATIONS PARP: Poly-ADP-Ribose Polymerase; VEGF: Vascular Endothelial Growth Factor; VEGFR: Vascular Endothelial Growth Factor Receptors; PDGF: Platelet-Derived Growth Factor; FGF: Fibroblast Growth Factor; HNSCC: Head and Neck Squamous Cell Carcinoma; ESCC: Esophageal Squamous Cell Carcinoma; FOXO: Forkhead box class O; XRCC1: X-ray Repair Cross- Complementing protein 1; BRCA2: Breast Cancer-Associated gene 2; HR: Homologous Recombination; NHEJ: Non-Homologous End Joining; GFP: Green Fluorescent Protein; CNV: Copy Number Variations; DSB: Double Strand Break; BRIP1: BRCA1-associated BACH1 helicase; LPS: Lipo Poly Saccharides; OS: Overall Survival; PFS: Progress Free Survival; HCC: HepatoCellular Carcinoma; EOC: Epithelial Ovarian Cancer; Alb/MTDH: A transgenic mouse with hepatocyte-specific expression of AEG-1 by directing the expression of human AEG-1 under an upstream enhancer region fused to the 335-base-pair core region of mouse albumin promoter. INTRODUCTION Although survival rate in gynecologic cancers have improved somewhat in the last decades, there are still many challenges including early diagnosis, prevention, drug resistance, metastasis and drug toxicity [1]. Tumor heterogeneity limits effective application of a standard single treatment modality in gynecologic cancers [2]. These complexities represent major challenges and impediments to developing effective cancer therapies. Newly emerging targeted molecular inhibitors, especially when used in combination with chemotherapy, are promising and may allow us to tailor treatment to individual patient and tumor genetic profiles [2,3]. Currently, mammalian target of rapamycin (mTOR) inhibitors, poly-ADP-ribose polymerase (PARP) inhibitors, tyrosine-kinase inhibitors for vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and components of the EGFR pathway are being tested in clinical trials for gynecologic cancers [4]. Identification of new molecule(s) that are key effectors of carcinogenesis and progression in many tumor types and which can be targeted therapeutically would be a significant advancement in the development of new treatments. We propose that two such molecules, FOXM1 [5-9] and MTDH [10-13], meet these criteria and can serve as novel diagnostic markers and therapeutic targets. Accumulated clinical and functional studies have demonstrated involvement of both FOXM1 and MTDH in cell proliferation, chemoresistance, angiogenesis, invasion, and metastasis in various types of human cancers. Therefore, FOXM1 and MTDH have been identified as prognostic markers. Overexpression of MTDH and FOXM1 in cancers Elevated FOXM1 expression has been reported in various types of malignancies including gynecologic cancers. Overexpression of FOXM1 has been observed in 87% of high-grade serous ovarian tumors [14]. FOXM1 has been identified as one of the most commonly upregulated genes in human solid tumors in several gene expression profiling studies. The forkhead box class O (FOXO) family is comprised of multifunctional transcription Ke ywo rds • FO XM1 • MTDH/ AEG -1/ LYRIC • NPM • ARF • DNA re p a ir • G yne c o lo g ic c a nc e rs • Ta rg e te d the ra p y Abstract Drug resistance and metastasis are the major challenges for treatment of gynecologic cancers. Tumor heterogeneity caused by diverse driver mutations in gynecologic cancers restricts the effective application targeted therapies. Both FOXM1 and MTDH are overexpressed and correlated with drug resistance and metastasis in various types of cancers including gynecologic cancers. Accumulated clinical and 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.