title: Cyclin E1 deregulation occurs early in secretory cell transformation to promote formation of fallopian tube-derived high-grade serous ovarian cancers.
abstract: The fallopian tube is now generally considered the dominant site of origin for high-grade serous ovarian carcinoma. However, the molecular pathogenesis of fallopian tube-derived serous carcinomas is poorly understood and there are few experimental studies examining the transformation of human fallopian tube cells. Prompted by recent genomic analyses that identified cyclin E1 (CCNE1) gene amplification as a candidate oncogenic driver in high-grade serous ovarian carcinoma, we evaluated the functional role of cyclin E1 in serous carcinogenesis. Cyclin E1 was expressed in early- and late-stage human tumor samples. In primary human fallopian tube secretory epithelial cells, cyclin E1 expression imparted malignant characteristics to untransformed cells if p53 was compromised, promoting an accumulation of DNA damage and altered transcription of DNA damage response genes related to DNA replication stress. Together, our findings corroborate the hypothesis that cyclin E1 dysregulation acts to drive malignant transformation in fallopian tube secretory cells that are the site of origin of high-grade serous ovarian carcinomas.
authors.affiliation: Authors' Affiliations: Department of Medical Oncology; Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute; Harvard Medical School; Department of Pathology, Division of Cytogenetics; Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Boston, Massachusetts; Peter MacCallum Cancer Centre, East Melbourne; Department of Oncology, Peter MacCallum Cancer Centre; Departments of Pathology and Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Karst
authors.forename: Paul M
authors.initials: PM
authors.lastname: Jones
authors.forename: Natalie
authors.initials: N
authors.lastname: Vena
authors.forename: Azra H
authors.initials: AH
authors.lastname: Ligon
authors.forename: Joyce F
authors.initials: JF
authors.lastname: Liu
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Hirsch
authors.forename: Dariush
authors.initials: D
authors.lastname: Etemadmoghadam
authors.forename: David D L
authors.initials: DD
authors.lastname: Bowtell
authors.forename: Ronny
authors.initials: R
authors.lastname: Drapkin
mesh_terms: D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019927:Cyclin E / Q000235:genetics* / Q000378:metabolism; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005185:Fallopian Tube Neoplasms / Q000235:genetics* / Q000473:pathology; D005187:Fallopian Tubes / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005784:Gene Amplification / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured
chemical_list: C475820:CCNE1 protein, human; D019927:Cyclin E; D015513:Oncogene Proteins