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, this positioning control is lost. The epithelial cell-derived cancer cells invade stroma and expand beyond the normal 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 of cells. The epithelial-expressed Disabled-2 is frequently lost in breast and ovarian tumor cells and is believed to be a tumor suppressor of relevance in ovarian cancer. Thus, inactivation of Disabled-2 is thought to lead to loss of positioning control and contributes to the neoplastic growth of the epithelial cells in ovarian cancer. We used a gene targeted knockout mouse model to examine the function of Disabled-2 in positioning control of epithelial cells. In mice where 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. The heterozygous Dab2 mutant mice are predisposed to uterine and ovarian hyperplasia and dysplasia. We propose the following investigations: 1) Determine the role of Disabled-2 and additional molecular events in morphological transformation using the epithelial transition zones of human ovarian tumor tissues; 2) Study the cellular function of Disabled-2 in cultured cells, particularly of its role in endocytosis and cargo targeting, which are essential to establish polarity in vivo;3) Create ovarian-specific conditional Disabled-2 deficient mice to determine if complete Disabled-2 inactivation causes neoplastic phenotype, and the synergy with inactivation of p53 in ovarian cancer development. The goals of the research are to validate the concept that disruption of epithelial structure, including polarity, is a critical component in epithelial neoplastic morphological transformation and to uncover the molecular details in the process of ovarian tumorigenicity. Such studies will lead to a better understanding of cancer etiology and will contribute to public health by providing cancer preventive stratagy and treatment therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095071-09
Application #
7841887
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2002-03-01
Project End
2012-05-31
Budget Start
2010-06-11
Budget End
2012-05-31
Support Year
9
Fiscal Year
2010
Total Cost
$323,942
Indirect Cost
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Smith, Elizabeth R; Meng, Yue; Moore, Robert et al. (2017) Nuclear envelope structural proteins facilitate nuclear shape changes accompanying embryonic differentiation and fidelity of gene expression. BMC Cell Biol 18:8
Tao, Wensi; Moore, Robert; Meng, Yue et al. (2016) Disabled-2 Determines Commitment of a Pre-adipocyte Population in Juvenile Mice. Sci Rep 6:35947
Capo-Chichi, Callinice D; Yeasky, Toni M; Smith, Elizabeth R et al. (2016) Nuclear envelope structural defect underlies the main cause of aneuploidy in ovarian carcinogenesis. BMC Cell Biol 17:37
Wang, Ying; Cai, Kathy Qi; Smith, Elizabeth R et al. (2016) Follicle Depletion Provides a Permissive Environment for Ovarian Carcinogenesis. Mol Cell Biol 36:2418-30
Tao, Wensi; Moore, Robert; Meng, Yue et al. (2016) Endocytic adaptors Arh and Dab2 control homeostasis of circulatory cholesterol. J Lipid Res 57:809-17
Tao, Wensi; Moore, Robert; Smith, Elizabeth R et al. (2016) Endocytosis and Physiology: Insights from Disabled-2 Deficient Mice. Front Cell Dev Biol 4:129
Moore, Robert; Tao, Wensi; Meng, Yue et al. (2014) Cell adhesion and sorting in embryoid bodies derived from N- or E-cadherin deficient murine embryonic stem cells. Biol Open 3:121-8
Tao, Wensi; Moore, Robert; Smith, Elizabeth R et al. (2014) Hormonal induction and roles of Disabled-2 in lactation and involution. PLoS One 9:e110737
Moore, Robert; Tao, Wensi; Smith, Elizabeth R et al. (2014) The primitive endoderm segregates from the epiblast in ?1 integrin-deficient early mouse embryos. Mol Cell Biol 34:560-72
Smith, Elizabeth R; Yang, Wan-Lin; Yeasky, Toni et al. (2013) Cyclooxygenase-1 inhibition prolongs postnatal ovarian follicle lifespan in mice. Biol Reprod 89:103

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