Chromosomal and genomic abnormalities affecting chromosome 16q have frequently been reported in cytogenetic and allelotypic studies of various epithelial tumors. We recently cloned and described WWOX, a gene spanning a genomic region of more than 1 MB located in ch. 16q23.3-24.1. This specific region is the most frequent target for LOH affecting 16q in breast, ovarian, prostate and other tumors. Others and we demonstrated that this is the very same region as that of the common chromosomal fragile site 16D (FRA16D). Translocation breakpoints common in multiple myeloma are also found within the WWOX genomic region. We determined that one of the WWOX alleles is inactivated very early in breast carcinogenesis and the vast majority of primary breast tumors and breast cancer lines display this abnormality. Homozygous deletions affecting WWOX exons were detected in ovarian carcinoma, and mutations affecting WWOX were reported in esophageal carcinoma. Recently, the occurrence of aberrantly and other cancer lines spliced forms affecting WWOX mRNA have also been reported to occur in multiple tumor types. In summary, evidence from various sources indicate that WWOX is a gene commonly affected at the genomic and transcriptional level in various tumor types. Recently, we demonstrated that ectopic WWOX expression strongly inhibits anchorage-independent growth of breast cancer cell lines, and induces a dramatic inhibition of tumorigenicity of the most aggressive breast cancer cell lines. We speculate that the normal cellular function of WWOX may be affected by various different mechanisms. Our hypothesis is that WWOX is an important cancer gene that can behave as a suppressor of tumor growth and that abnormalities affecting this gene at the genomic and transcriptional level are relevant in carcinogenesis. Thus, we propose in Aim 1: To generate mouse strains containing WWOX disrupted alleles. We will A) generate a conditionally targeted WWOX mutant allelic series utilizing the cre-lox and tip-fit recombinase system and B) generate mice expressing a WWOX-LacZ fusion protein product of disruption of the endogenous WWOX alleles. This truncated WWOX form will be similar to that produce in various tumor types.
Aim 2 : To identify WWOX protein domains important for tumor inhibition and cellular localization. To this end mutant WWOX forms will be created affecting the WW domains and critical portions of the oxidoreductase enzymatic domain.
Aim 3 : To identify cellular proteins that interact with WWOX. Various candidate in vitro WWOX binding proteins containing the matching PPXP motifs have been already identified and cloned. Various approaches will be followed to define the true in vivo interacting proteins.
Aim 4 : To determine patterns and levels of WWOX protein expression in breast and ovarian carcinomas assessing its relevance as a prognostic tool.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102444-04
Application #
7111770
Study Section
Pathology B Study Section (PTHB)
Program Officer
Yassin, Rihab R,
Project Start
2003-09-01
Project End
2008-06-30
Budget Start
2006-07-10
Budget End
2007-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$328,079
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Organized Research Units
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Schrock, M S; Batar, B; Lee, J et al. (2017) Wwox-Brca1 interaction: role in DNA repair pathway choice. Oncogene 36:2215-2227
Abba, Martin C; Gong, Ting; Lu, Yue et al. (2015) A Molecular Portrait of High-Grade Ductal Carcinoma In Situ. Cancer Res 75:3980-90
Iatan, Iulia; Choi, Hong Y; Ruel, Isabelle et al. (2014) The WWOX gene modulates high-density lipoprotein and lipid metabolism. Circ Cardiovasc Genet 7:491-504
Aldaz, C Marcelo; Ferguson, Brent W; Abba, Martin C (2014) WWOX at the crossroads of cancer, metabolic syndrome related traits and CNS pathologies. Biochim Biophys Acta 1846:188-200
Mallaret, Martial; Synofzik, Matthis; Lee, Jaeho et al. (2014) The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation. Brain 137:411-9
Ferguson, Brent W; Gao, Xinsheng; Zelazowski, Maciej J et al. (2013) The cancer gene WWOX behaves as an inhibitor of SMAD3 transcriptional activity via direct binding. BMC Cancer 13:593
Ferguson, Brent W; Gao, Xinsheng; Kil, Hyunsuk et al. (2012) Conditional Wwox deletion in mouse mammary gland by means of two Cre recombinase approaches. PLoS One 7:e36618
Ludes-Meyers, John H; Kil, Hyunsuk; Parker-Thornburg, Jan et al. (2009) Generation and characterization of mice carrying a conditional allele of the Wwox tumor suppressor gene. PLoS One 4:e7775
Pimenta, Flavio Juliano; Cordeiro, Gabriela Tavares; Pimenta, Luiz Gustavo Garcia Santos et al. (2008) Molecular alterations in the tumor suppressor gene WWOX in oral leukoplakias. Oral Oncol 44:753-8
Ramos, D; Abba, M; Lopez-Guerrero, J A et al. (2008) Low levels of WWOX protein immunoexpression correlate with tumour grade and a less favourable outcome in patients with urinary bladder tumours. Histopathology 52:831-9

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