Receptor tyrosine kinase (RTK) signaling pathways are crucial to the initiation and progression of many different types of cancer. Sprouty genes are known negative feedback regulators of RTK signaling pathways. Four Sprouty genes have been identified, three of which are predominantly expressed in most tissues (e.g. Sprouty1, Sprouty2, Sprouty4). The exact mechanism by which Sprouty gene products function is not wel understood. However, there is a significant amount of published literature that links low Sprouty gene expression with human cancers, suggesting that Sprouty genes may act as tumor suppressors (genes that suppress tumor growth). Most of this research is based on association studies, making it difficult to know with certainty whether decreased Sprouty expression occurs before or after tumors form. Additionally, many of these studies focused on deleting one, sometimes two, Sprouty genes to assess their function as tumor suppressors. Since it is not clear if Sprouty genes are able to compensate for one another when expression of one Sprouty gene is silenced, we may not yet appreciate the full impact that this family of genes has on preventing tumors from forming. A systems genetics study has shown that increased levels of Sprouty2 expression in mouse skin are protective against the formation of skin tumors24. In order to explore the role that Sprouty genes may play in preventing skin cancer, I will use genetically modified mice that lack gene expression from the three most predominantly expressed Sprouty genes. These mice will be treated with carcinogens that cause skin tumors to form. If Sprouty genes are tumor suppressors in the skin, I expect to see more tumors form in mice that are missing the three Sprouty genes compared to normal mice. This genetic mouse skin cancer model will allow me to directly test if Sprouty genes prevent cancer in the skin. Additionally, in order to explore the effects of inactivating Sprouty genes at the cellular level, I will isolate mouse skin stem cells that lack Sprouty genes and perform several biochemical experiments on them. Understanding the underlying biological effects of Sprouty genes will increase our knowledge of both skin and cancer biology, and could provide clues about future therapeutic targets for skin cancer.

Public Health Relevance

Cancer is a disease that affects millions of people worldwide every year. It is caused by normal cells that begin to divide and multiply uncontrollably. Identifying genes that cause normal cells to transform into cancerous ones will enable us to identify new treatments that will someday eradicate this terrible disease.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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NIDCR Special Grants Review Committee (DSR)
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Frieden, Leslie A
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University of California San Francisco
Schools of Dentistry
San Francisco
United States
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