Mechanistic or mammalian target of rapamycin (mTOR) is a central controller of cell growth and proliferation in response to mitogenic and nutrient signals. mTOR pathway is frequently hyper-activated in human cancers, leading to uncontrolled cancer growth. Because cancer cells are often 'addicted'to elevated mTOR signaling, rendering mTOR a desirable cancer drug target. The highly specific mTOR inhibitors rapamycin analogs (rapalogs) are FDA-approved anti-cancer drugs for advanced renal and breast cancers. However, their efficacy is limited by lack of understanding of what patients are responsive to rapalog therapy. Therefore, a detailed understanding of mTOR signaling will is of considerable significance to basic biology and cancer therapy. In this application, we will investigate the mechanism of stimulation of cell growth and cancer by Rab1, a novel mTOR activator we recently identified. We will further study the role of Rab1 in the pathobiology and targeted therapy of breast cancer. We anticipate that successful completion of this project will help answer some long-standing questions on cell regulation and enable individualized cancer therapy.

Public Health Relevance

This project will investigate how cells modulate the growth engine in response to external stimuli. We will study a novel mechanism in this process, which should provide important new insights into long- standing questions in cell biology. Moreover, we will determine how dysfunction of this process can cause human breast cancer and influence the outcome of targeted breast cancer therapy. If successful, our research will help understand the underlying pathobiology and lead to new treatment of breast malignancies. It will also have implications for other types of cancer as well as diseases such as cardiac hypertrophy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Spalholz, Barbara A
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Rbhs -Cancer Institute of New Jersey
New Brunswick
United States
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Li, Yue; Tsang, Chi Kwan; Wang, Suihai et al. (2016) MAF1 suppresses AKT-mTOR signaling and liver cancer through activation of PTEN transcription. Hepatology 63:1928-42
Yang, X-Z; Li, X-X; Zhang, Y-J et al. (2016) Rab1 in cell signaling, cancer and other diseases. Oncogene 35:5699-5704
Che, Meixia; Wang, Ren; Li, Xiaoxing et al. (2016) Expanding roles of superoxide dismutases in cell regulation and cancer. Drug Discov Today 21:143-9
Xu, Bi-Hong; Li, Xiao-Xing; Yang, Yang et al. (2015) Aberrant amino acid signaling promotes growth and metastasis of hepatocellular carcinomas through Rab1A-dependent activation of mTORC1 by Rab1A. Oncotarget 6:20813-28
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Thomas, Janice D; Zhang, Yan-Jie; Wei, Yue-Hua et al. (2014) Rab1A is an mTORC1 activator and a colorectal oncogene. Cancer Cell 26:754-69