The majority of breast cancer deaths result from the progression of this disease to a metastatic phenotype. Rac1 and Cdc42 are Rho family members that together with their downstream effectors, Wiskott-Aldrich Syndrome protein-family verprolin-homologous protein 2 (WAVE2) and Arp2/3, play an important role in cytoskeletal reorganization and the formation of membrane protrusions that promote cancer cell migration and invasion. γ-Tocotrienol, is a natural isoform within the vitamin E family of compounds that inhibits breast cancer cell growth and progression by suppressing various signaling pathways involved in mitogenic signaling and metastatic progression. Studies were conducted to examine the effects of γ-tocotrienol on Rac1/WAVE2 signaling dependent migration and invasion in highly metastatic mouse SA and human MDA-MB-231 mammary cancer cells. Exposure to γ-tocotrienol resulted in a dose-responsive decrease in Rac1/WAVE2 signaling as characterized by a suppression in the levels of Rac1/Cdc42, phospho-Rac1/Cdc42, WAVE2, Arp2, and Arp3 expression. Additional studies also demonstrated that similar treatment with γ-tocotrienol resulted in a significant reduction in tumor cell migration and invasion. Taken together, these findings indicate that γ-tocotrienol treatment effectively inhibits Rac1/WAVE2 signaling and reduces metastatic phenotypic expression in mammary cancer cells, suggesting that γ-tocotrienol may provide some benefit as a novel therapeutic approach in the treatment of metastatic breast cancer.Key words γ-tocotrienol; breast cancer; Rac1; Wiskott-Aldrich Syndrome protein-family verprolin-homologous protein 2 (WAVE2); migration; invasion Breast cancer is the most common form of cancer in women and is second only to lung cancer as a leading cause of cancer mortality in the United States.1,2) The vast majority of breast cancer deaths result from the development and progression of the metastatic form of this disease, that is characterized by cancer cells detaching from the primary tumor and spreading to distant sites in the body such as the bone, brain, surrounding lymph nodes, liver, and lungs.3-5) Breast cancer metastasis is a complex and multistep process that includes morphological changes, detachment from the basement membrane, increased mobility and invasion into surrounding tissues, intravasation, circulation, adhesion, extravasation, and growth at distant sites. 6) Since patient prognosis for metastatic breast cancer is very poor, there is great interest in developing antiinvasion therapies to improve patient treatment and survival.
7)An initial step in the metastasis process involves epithelialto-mesenchymal transition (EMT), where neoplastic epithelial cells lose their cellular polarity and acquire mesenchymal-like mobility that allows them to invade surrounding tissues. [8][9][10][11] This amoeboid-like movement requires the formation of cellular protrusions that result from the conversion of monomeric globular actin (G-actin) to polymerized filamentous actin (Factin).
12-15)The Rho family of sm...
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