Epithelial Positioning Organization and Ovarian Cancer

Project: Research project

Description

A prominent hallmark of malignant solid tumors is disorganization: in normal tissues, epithelial cells are positionally organized along a sheet of basement membrane and in tumors, the positioning control is lost. The epithelial cell- derived carcinoma cells invade stroma and expand beyond tissue structure, damaging and interfering with the physiological functions of the organs. Genes such as Disabled-1 and Disabled-2 may function in the positioning organization of cells. Gene- targeted knockouts in mice have established the role of Disabled- 1 in brain cell positioning control and the signaling pathway involved. The epithelial-expressed Disabled-2 is frequently lost in breast and ovarian tumor cells and is believed to be a tumor suppressor of ovarian cancer. Disabled-2 is similar to Disabled- 1 in structure and biochemical function, and accumulating information supports a role for Disabled-2 in epithelial cell positioning organization. Thus, it is thought that inactivation of Disabled-2 in ovarian cancer leads to loss of positioning control and contributes to the malignant growth of the epithelial cells. We used a gene targeted knockout mouse model to examine the function of Disabled-2 in positioning control of ovarian surface epithelial cells. In mice that Disabled-2 is disrupted by an in-frame replacement/insertion of beta-galactosidase (LacZ), disruption of both copies of Disabled-2 gene results in early embryonic lethality, likely due to its requirement in visceral endoderm cell positioning organization. We propose the following investigations: 1) Determine the role of Disabled-2 in early embryonic development; 2) Determine the tissue expression pattern and developmental regulation of Disabled-2 using heterozygous LacZ-replacement mice; 3) Determine if there is a predisposition in heterozygous Disabled-2 mutant mice to develop ovarian malignancy; 4) Create tissue-specific conditional Disabled-2 deficient mice to determine if Disabled-2 deficiency contributes to the loss of ovarian surface epithelial cell organization and tumorigenicity.
StatusFinished
Effective start/end date3/1/025/31/12

Funding

  • National Institutes of Health: $373,800.00
  • National Institutes of Health: $323,942.00
  • National Institutes of Health: $372,866.00
  • National Institutes of Health: $94,503.00
  • National Institutes of Health: $124,129.00
  • National Institutes of Health: $307,831.00
  • National Institutes of Health: $323,942.00
  • National Institutes of Health: $136,963.00
  • National Institutes of Health: $85,680.00
  • National Institutes of Health: $373,800.00
  • National Institutes of Health: $374,915.00
  • National Institutes of Health: $127,853.00
  • National Institutes of Health: $225,090.00

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Ovarian Neoplasms
Epithelial Cells
Neoplasms
Gene Knockout Techniques
Knockout Mice
Endoderm
beta-Galactosidase
Basement Membrane
Genes
Growth
Endocytosis
Breast Neoplasms
Embryonic Development
Cultured Cells
Public Health
Carcinoma
Phenotype

ASJC

  • Medicine(all)