The Wnt gene family has been implicated in normal mammary gland development, as well as in tumorigenesis in animal models and there is recent indirect evidence for perturbations of their signaling pathways in some cancer malignancies. However, investigation of Wnt genes and their role in human breast cancer have been severely hampered because their cell surface receptors have not yet been identified. A very recent major breakthrough strongly implicates membrane spanning molecules encoded by the multi gene frizzled family as their receptors. The applicant has developed novel approaches involving chimeric Wnt-IgG proteins to further study Wnt receptors. A major aim of this proposal is to establish the identity of the Wnt-2 receptor as a frizzled gene(s) using cells known to be susceptible to Wnt-2 transforming effects as the source. The applicant will then perform a systematic analysis of oncogenic activation of Wnt family members and their receptors in human breast tumors. Approaches will involve investigation of the role of autocrine transformation and alterations including gene amplification or other structural gene alterations that activate Wnt receptors. The applicant will also develop models in tissue culture to confirm that the genetic alterations observed contribute to neoplastic progression. Finally, the applicant will seek to gain insights into biochemical signaling properties of these receptors to aid in uncovering other aberrations in tumor cells. The molecular and immunologic reagents generated can then be assessed for their utility as molecular markers in diagnosis and/or prognosis of breast cancer.
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