title: The High Mobility Group A1 (HMGA1) gene is highly overexpressed in human uterine serous carcinomas and carcinosarcomas and drives Matrix Metalloproteinase-2 (MMP-2) in a subset of tumors.
abstract: Although uterine cancer is the fourth most common cause for cancer death in women worldwide, the molecular underpinnings of tumor progression remain poorly understood. The High Mobility Group A1 (HMGA1) gene is overexpressed in aggressive cancers and high levels portend adverse outcomes in diverse tumors. We previously reported that Hmga1a transgenic mice develop uterine tumors with complete penetrance. Because HMGA1 drives tumor progression by inducing MatrixMetalloproteinase (MMP) and other genes involved in invasion, we explored the HMGA1-MMP-2 pathway in uterine cancer.
  
  
  
  To investigate MMP-2 in uterine tumors driven by HMGA1, we used a genetic approach with mouse models. Next, we assessed HMGA1 and MMP-2 expression in primary human uterine tumors, including low-grade carcinomas (endometrial endometrioid) and more aggressive tumors (endometrial serous carcinomas, uterine carcinosarcomas/malignant mesodermal mixed tumors).
  
  
  
  Here, we report for the first time that uterine tumor growth is impaired in Hmga1a transgenic mice crossed on to an Mmp-2 deficient background. In human tumors, we discovered that HMGA1 is highest in aggressive carcinosarcomas and serous carcinomas, with lower levels in the more indolent endometrioid carcinomas. Moreover, HMGA1 and MMP-2 were positively correlated, but only in a subset of carcinosarcomas. HMGA1 also occupies the MMP-2 promoter in human carcinosarcoma cells.
  
  
  
  Together, our studies define a novel HMGA1-MMP-2 pathway involved in a subset of human carcinosarcomas and tumor progression in murine models. Our work also suggests that targeting HMGA1 could be effective adjuvant therapy for more aggressive uterine cancers and provides compelling data for further preclinical studies.
authors.affiliation: Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.
authors.forename: Joelle
authors.initials: J
authors.lastname: Hillion
authors.affiliation: Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.
authors.forename: Sujayita
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Biologic Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Heydarian
authors.affiliation: Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.
authors.forename: Leslie
authors.initials: L
authors.lastname: Cope
authors.affiliation: Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.
authors.forename: Lingling
authors.initials: L
authors.lastname: Xian
authors.affiliation: Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Koo
authors.affiliation: Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.
authors.forename: Li Z
authors.initials: LZ
authors.lastname: Luo
authors.affiliation: Pathobiology Graduate Program, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Kellyn
authors.affiliation: Pathobiology Graduate Program, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.
authors.forename: Brigitte M
authors.initials: BM
authors.lastname: Ronnett
authors.affiliation: Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.
authors.forename: Tait
authors.initials: T
authors.lastname: Huso
authors.affiliation: Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.
authors.forename: Deborah
authors.initials: D
authors.lastname: Armstrong
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Biologic Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Reddy
authors.affiliation: Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.affiliation: Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Pathobiology Graduate Program, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; Institute for Cellular Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, United States. Electronic address: lresar@jhmi.edu.
authors.forename: L M S
authors.initials: LMS
authors.lastname: Resar
mesh_terms: D000818:Animals; D002296:Carcinosarcoma / Q000235:genetics* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D025741:HMGA1a Protein / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics*; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D015854:Up-Regulation; D014594:Uterine Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: D025741:HMGA1a Protein; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
keywords: Chromatin remodeling proteins; HMGA1; High Mobility Group A1; MMP-2; Tumor progression; Uterine cancer