Ras family GTPases involved in breast cancer
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Hanker, Ariella Binah. Ras Family Gtpases Involved In Breast Cancer. 2009. https://doi.org/10.17615/b25z-wv76APA
Hanker, A. (2009). Ras family GTPases involved in breast cancer. https://doi.org/10.17615/b25z-wv76Chicago
Hanker, Ariella Binah. 2009. Ras Family Gtpases Involved In Breast Cancer. https://doi.org/10.17615/b25z-wv76- Last Modified
- March 21, 2019
- Creator
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Hanker, Ariella Binah
- Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
- Abstract
- The Ras branch of the Ras superfamily of small GTPases consists of over thirty-six proteins that regulate a wide array of cellular processes. Mutations in the RAS oncogene that cause aberrant activation of Ras signaling drive 30% of all cancers, but these mutations are infrequent in breast cancer. Instead, other Ras family proteins may play more significant roles in the development and progression of breast cancer. Here, we focus on two such proteins, Rerg and Rheb. Hyperactive Rheb activity may enhance breast cancer tumorigenesis, whereas Rerg has been proposed to negatively regulate breast cancer growth. Expression of Rerg is controlled by estrogen; hence, Rerg is not expressed in estrogen receptor-negative breast cancers. Whether loss of Rerg expression in these tumors contributes to breast cancer progression is not known. We found that silencing Rerg expression did not significantly enhance the growth or invasive properties of breast cancer cells, and likewise, inducing Rerg expression in Rerg-negative breast cancer cell lines did not diminish their growth. Thus, these studies argue against a role for Rerg as a tumor suppressor in breast cancer. More studies are needed to determine whether Rerg is involved in breast cancer in vivo. Rheb and its effector mTOR have been strongly implicated in the development of many cancers, including breast cancer. Upstream regulators of Rheb are commonly activated in the majority of breast cancers, leading to increased Rheb activity in breast cancer. However, approaches to inhibit Rheb function in breast cancer have not been comprehensively explored. Here, we investigated two strategies to inhibit Rheb-mTOR signaling. First, we asked whether CAAX-mediated posttranslational processing of Rheb is required for its function. We found that, while farnesylation is absolutely required for Rheb activation of mTOR, post-prenyl processing by the enzymes Rce1 and Icmt is dispensable for Rheb signaling. Our studies further suggested that endomembrane localization of Rheb is not required for its activation of mTOR. Finally, we found that the farnesylcysteine mimetic S-trans, trans-farnesylthiosalicylic acid (FTS; salirasib) did not block Rheb localization, but potently inhibited mTOR-induced p70 S6 kinase (S6K) activation, suggesting that FTS is a direct inhibitor of mTOR. Therefore, FTS may be a promising therapy for the treatment of Rheb- and mTOR-dependent cancers, including breast cancer. Together, these studies have increased our understanding of the functions of Rerg and Rheb in breast cancer and have suggested a potential therapeutic strategy to reverse aberrant Rheb signaling in breast cancer.
- Date of publication
- August 2009
- DOI
- Resource type
- Rights statement
- In Copyright
- Advisor
- Der, Channing
- Degree granting institution
- University of North Carolina at Chapel Hill
- Language
- Access right
- Open access
- Date uploaded
- October 11, 2010
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