WOX IN BREAST CANCER

"Contribution of the WW domain-containing oxidoreductase, WWOX, gene toward mammary tumorigenesis"

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 Obiettivo del progetto (Objective)

'Chromosomal and genomic abnormalities affecting chromosome 16q have frequently been reported in cytogenetic and allelotypic studies of various epithelial tumors, including breast cancer. The WWOX gene has been recently cloned and described. WWOX spans a genomic region of more than 1 MB located in ch. 16q23.1. This specific region is the most frequent target for LOH affecting 16q in breast cancer. The critical role of WWOX in breast cancer was recently highlighted by the suppression of tumor growth in mice and formation of spontaneous tumors in targeted Wwox heterozygous mice. Biochemical studies demonstrated that Wwox suppresses the transactivation ability of interacting oncoproteins that are well implicated in breast cancer. While our data and others show that Wwox is critical for breast cancer onset, it is not clear the role of Wwox in normal development of mammary gland and its contribution toward breast tumorigenesis. Obviously, understanding how Wwox functions to suppress tumorigenesis will be essential for the future development of effective breast cancer therapies. Our hypothesis is that WWOX is an important breast cancer gene that suppresses tumor growth and that abnormalities affecting this gene at the genomic, transcriptional and protein levels are relevant in carcinogenesis. Thus, we propose to engineer a mouse model that lack the expression of Wwox in mammary gland epithelium and to investigate the mechanism underlying Wwox function contributing to breast cancer. In Aim1, we will generate a mouse model that lacks expression of Wwox in mammary cells. In Aim2, we will utilize the mouse model from Aim1 to study the contribution of Wwox toward mammary tumorigenesis. In Aim3, we will study Wwox candidate interacting proteins to better understand how Wwox functions to suppress mammary tumor growth. The proposed study will elucidate the mechanism of Wwox action in breast cancer and will identify Wwox as important novel therapeutic target for cancer intervention'