title: HE4 (WFDC2) gene overexpression promotes ovarian tumor growth.
abstract: Selective overexpression of Human epididymal secretory protein E4 (HE4) points to a role in ovarian cancer tumorigenesis but little is known about the role the HE4 gene or the gene product plays. Here we show that elevated HE4 serum levels correlate with chemoresistance and decreased survival rates in EOC patients. HE4 overexpression promoted xenograft tumor growth and chemoresistance against cisplatin in an animal model resulting in reduced survival rates. HE4 displayed responses to tumor microenvironment constituents and presented increased expression as well as nuclear translocation upon EGF, VEGF and Insulin treatment and nucleolar localization with Insulin treatment. HE4 interacts with EGFR, IGF1R, and transcription factor HIF1α. Constructs of antisense phosphorothio-oligonucleotides targeting HE4 arrested tumor growth in nude mice. Collectively these findings implicate increased HE4 expression as a molecular factor in ovarian cancer tumorigenesis. Selective targeting directed towards the HE4 protein demonstrates therapeutic benefits for the treatment of ovarian cancer.
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Women and Infants' Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, RI 02903, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Moore
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Women and Infants' Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, RI 02903, USA.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Hill
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Women and Infants' Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, RI 02903, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Horan
authors.affiliation: Department of Pediatrics, Women and Infants' Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, RI 02903, USA.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yano
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Women and Infants' Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, RI 02903, USA.
authors.forename: KyuKwang
authors.initials: K
authors.lastname: Kim
authors.affiliation: Stanford School of Medicine, Gynecology Oncology, 300 Pasteur Dr. A370 Stanford, CA 94305, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: MacLaughlan
authors.affiliation: Prenatal and Special Testing, Department of Pathology, Women and Infants' Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, Rhode Island, USA.
authors.forename: Geralyn
authors.initials: G
authors.lastname: Lambert-Messerlian
authors.affiliation: Department of Pediatrics, Women and Infants' Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, RI 02903, USA.
authors.forename: YiTang Don
authors.initials: YD
authors.lastname: Tseng
authors.affiliation: Department of Pediatrics, Women and Infants' Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, RI 02903, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Padbury
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Women and Infants' Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, RI 02903, USA.
authors.forename: M Craig
authors.initials: MC
authors.lastname: Miller
authors.affiliation: 1] Molecular Therapeutics Laboratory, Program in Women's Oncology, Women and Infants' Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, RI 02903, USA [2] Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Thilo S
authors.initials: TS
authors.lastname: Lange
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Women and Infants' Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, RI 02903, USA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002455:Cell Division / Q000235:genetics*; D002945:Cisplatin / Q000627:therapeutic use; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy / Q000473:pathology*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D000081102:WAP Four-Disulfide Core Domain Protein 2
chemical_list: D000970:Antineoplastic Agents; D011506:Proteins; D000081102:WAP Four-Disulfide Core Domain Protein 2; C569698:WFDC2 protein, human; D002945:Cisplatin