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      Mutant p53 expression in fallopian tube epithelium drives cell migration

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          Abstract

          Ovarian cancer is the fifth leading cause of cancer death among US women. Evidence supports the hypothesis that high-grade serous ovarian cancers (HGSC) may originate in the distal end of the fallopian tube. Although a heterogeneous disease, 96% of HGSC contain mutations in p53. In addition, the “p53 signature”, or overexpression of p53 protein (usually associated with mutation), is a potential precursor lesion of fallopian tube derived HGSC suggesting an essential role for p53 mutation in early serous tumorigenesis. To further clarify p53-mutation dependent effects on cells, murine oviductal epithelial cells (MOE) were stably transfected with a construct encoding for the R273H DNA binding domain mutation in p53, the most common mutation in HGSC. Mutation in p53 was not sufficient to transform MOE cells, but did significantly increase cell migration. A similar p53 mutation in murine ovarian surface epithelium (MOSE), another potential progenitor cell for serous cancer, was not sufficient to transform the cells nor change migration suggesting tissue specific effects of p53 mutation. Microarray data confirmed expression changes of pro-migratory genes in p53 R273H MOE compared to parental cells, which could be reversed by suppressing Slug expression. Combining p53 R273H with KRAS G12V activation caused transformation of MOE into high-grade sarcomatoid carcinoma when xenografted into nude mice. Elucidating the specific role of p53 R273H in the fallopian tube will improve understanding of changes at the earliest stage of transformation and could help develop chemopreventative strategies to prevent the accumulation of additional mutations and reverse progression of the “p53 signature” thereby, improving survival rates.

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          Author and article information

          Journal
          0042124
          4284
          Int J Cancer
          Int. J. Cancer
          International journal of cancer. Journal international du cancer
          0020-7136
          1097-0215
          22 May 2015
          11 April 2015
          1 October 2015
          01 October 2016
          : 137
          : 7
          : 1528-1538
          Affiliations
          [1 ]Department of Medicinal Chemistry and Pharmacognosy, Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60607, USA
          [2 ]Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
          Author notes
          Corresponding author: Joanna E Burdette, Address: 900 S. Ashland Ave (M/C 870), Chicago, IL 60607, Telephone: 312-996-6153, Fax: 312-996-7107, joannab@ 123456uic.edu
          Article
          PMC4503498 PMC4503498 4503498 nihpa678770
          10.1002/ijc.29528
          4503498
          25810107
          8d8297ce-eba7-444f-8c28-a113446f4e48
          History
          Categories
          Article

          high-grade serous cancer,p53 mutation,fallopian tube

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