title: Epiregulin contributes to breast tumorigenesis through regulating matrix metalloproteinase 1 and promoting cell survival.
abstract: BACKGROUND
  The epidermal growth factor (EGF) family of ligands has been implicated in promoting breast cancer initiation, growth and progression. The contributions of EGF family ligands and their receptors to breast cancer are complex, and the specific mechanisms through which different ligands regulate breast tumor initiation and growth are not well-defined. These studies focus on the EGF family member epiregulin (EREG) as a mediator of early stage breast tumorigenesis.
  
  
  METHODS
  EREG expression levels were assessed in both cell lines and human samples of ductal carcinoma in situ (DCIS) using quantitative RT-PCR, ELISA and immunohistochemistry. Gene knock-down approaches using shRNA-based strategies were used to determine the requirement of EREG for growth of MCF10DCIS cells in vivo, and for identifying mechanisms through which EREG promotes tumor cell survival. Experiments were performed using a combination of two-dimensional culture, three-dimensional culture and tumor growth in vivo.
  
  
  RESULTS
  In comparison with other EGF family members, EREG was induced in MCF10DCIS cells compared with MCF10A and MCF10AT cells and its expression was partially regulated by fibroblast growth factor receptor (FGFR) activity. Reduced EREG expression in MCF10DCIS cells led to decreased tumor growth in vivo, which was associated with reduced cell survival. Furthermore, treatment of MCF10A cells with exogenous EREG enhanced cell survival both in three-dimensional culture and in response to chemotherapeutic agents. Examination of EREG-induced signaling pathways demonstrated that EREG promoted survival of MCF10A cells through regulating expression of matrix metalloproteinase-1 (MMP-1). To determine the relevance of these findings in human tumors, samples of DCIS were analyzed for EREG and MMP-1 expression. EREG was induced in DCIS lesions compared to normal breast epithelium, and EREG and MMP-1 were correlated in a subset of DCIS samples.
  
  
  CONCLUSIONS
  Together, these studies lead to identification of a novel pathway involving EREG and MMP-1 that contributes to the formation of early stage breast cancer. Understanding these complex pathways could ultimately lead to the development of novel biomarkers of neoplastic progression and/or new therapeutic strategies for patients with early stage cancer.
authors.affiliation: Department of Lab Medicine and Pathology, University of Minnesota, 2231 6th St SE, Minneapolis, MN, 55455, USA.
authors.forename: Mariya
authors.initials: M
authors.lastname: Farooqui
authors.affiliation: Department of Lab Medicine and Pathology, University of Minnesota, 2231 6th St SE, Minneapolis, MN, 55455, USA.
authors.forename: Laura R
authors.initials: LR
authors.lastname: Bohrer
authors.affiliation: Microbiology, Immunology and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, MN, 55455, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brady
authors.affiliation: Microbiology, Immunology and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, MN, 55455, USA.
authors.forename: Pavlina
authors.initials: P
authors.lastname: Chuntova
authors.affiliation: Department of Lab Medicine and Pathology, University of Minnesota, 2231 6th St SE, Minneapolis, MN, 55455, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Kemp
authors.affiliation: College of Veterinary Medicine, University of Minnesota, Minneapolis, MN, 55455, USA.
authors.forename: C Taylor
authors.initials: CT
authors.lastname: Wardwell
authors.affiliation: Department of Lab Medicine and Pathology, University of Minnesota, 2231 6th St SE, Minneapolis, MN, 55455, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Nelson
authors.affiliation: Department of Lab Medicine and Pathology, University of Minnesota, 2231 6th St SE, Minneapolis, MN, 55455, USA. schwe251@umn.edu.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA. schwe251@umn.edu.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Schwertfeger
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D066260:Epiregulin / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis* / Q000235:genetics; D009367:Neoplasm Staging; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics
chemical_list: C587880:EREG protein, human; D066260:Epiregulin; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1