WOX IN BREAST CANCER · Contribution of the WW domain-containing oxidoreductase, WWOX, gene toward mammary tumorigenesis
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2008-03-01 → 2012-02-29
- Финансиране от ЕС
- 100 000 €
- Участници
- 1
- Схема
- MC-IRG
Линиите свързват координатора с партньорите.
Накратко на български
Генът WWOX и неговата роля при развитието на рак на гърдата се анализират чрез използването на специално създадени мишки. Това помага да се разбере как липсата на този протеин влияе върху образуването на тумори и клетъчния баланс.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Contribution of the WW domain-containing oxidoreductase, WWOX, gene toward mammary tumorigenesis
WWOX in breast carcinogenesis. The WWOX gene encodes a 46kDa tumor suppressor spanning a genomic region that is frequently altered in breast cancer. Homozygous and hemizygous deletions were reported in several types of cancer including breast cancer. Numerous studies have shown that overexpression of WWOX in breast cancer cells renders them more sensitive to apoptosis and resistant to tumor formation in nude mice. Monitoring of Wwox-heterozygous mice in partially pure C3H background mice revealed increased incidence of mammary tumor formation as compared to control wild type littermates (1). These results and others promoted us to address the specific contribution of WWOX to mammary tumorigenesis. We took advantage of mouse models and generated a conditional-knockout mouse to ablate the Wwox gene specifically in mammary gland epithelium. Successful generation and validation of the mouse model was completed. Using this model, we aim to examine the consequences of WWOX deletion on mammary gland development and tumorigenesis. We also performed a proteomic experiment to identify WWOX partners that explain WWOX tumor suppressor activity in breast cancer cells. Our analysis revealed novel hits that help understanding the complex contribution of WWOX toward several phenotypes in homeostasis and in cancer (2). 1. Abdeen S, Salah Z, Mally B, Smith Y, Tufail, R, Abu-Odeh M, Zanesi N, Croce CM, Nawaz Z, Aqeilan RI. Wwox inactivation enhances mammary tumorigenesis. Oncogene. 2011; 30(36):3900-6. 2. Del Mare S, Salah Z, Aqeilan RI: Wwox: Its genomics, partners, and functions. J Cell Biochem 2009;108:737-745.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
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
Оригинален текст от CORDIS (на английски).
Участници
- THE HEBREW UNIVERSITY OF JERUSALEM · JerusalemКоординаторИзраел
Връзки
Данни: CORDIS, © Европейски съюз