rapamycin and mtor a serendipitous discovery and implications for breast cancer雷帕霉素和mtor偶然的发现和对乳腺癌的影响.pdfVIP

Seto Clinical and Translational Medicine 2012, 1:29 /content/1/1/29 REVIEW Open Access Rapamycin and mTOR: a serendipitous discovery and implications for breast cancer Belinda Seto Abstract Rapamycin was discovered more than thirty years ago from a soil sample from the island of Rapa Nui. It was isolated from Streptomyces hygroscopicus and initial characterization focused on its antifungal activities. Subsequent characterization showed that it has immunosuppressive properties and has been used successfully to reduce organ rejection with kidney transplantation. Rapamycin has proven to be a versatile compound with several seemingly unrelated properties, including antifungal, immunosuppressive, and anticancer. The National Cancer Institute (NCI) Developmental Therapeutics Program demonstrated that rapamycin inhibited cell growth in tumor cell lines. These observations stimulated research to explore the underlying mechanism of anti-tumor activities. Cell growth inhibition involves binding to the mammalian Target of Rapamycin (mTOR). The mTOR signaling pathway is critical to cell growth, proliferation, and survival and rapamycin inhibits these hallmark processes of cancer. Binding of growth factors activates mTOR signaling, which in turn leads to downstream phosphorylation of protein kinases, e.g., p70S6 kinase and lipid kinases in the phosphorylation of phosphoinositides. Understanding of mTOR signaling provided the biological basis for targeted chemotherapeutics development, including several rapamycin analogues for treating breast and other cancers. Keywords: Rapamycin, Mammalian Target of Rapamycin (mTOR), Breast cancer, Targeted chemotherapeutics, Clinical translation Review This report describes a tale of discovery that reinforces