The alpha6beta4 integrin combines with RTKs, such as ErbB2 and Met, to promote cell survival, proliferation and migration. To examine the role of alpha6beta4 signaling in prostate cancer, we have generated mice carrying a targeted deletion of the beta4 signaling domain. These mice display defective wound healing and angiogenesis. Wild type and beta4 mutant mice have been intercrossed to TRAMP mice, which develop prostate cancer upon Probasin-mediated expression of the T Ag. Comparison of tumor onset and progression in the two cohorts of mice has revealed that beta4 signaling is necessary for efficient transition from high-grade PIN to invasive carcinoma.
Our specific aims are: 1) To examine the mechanisms by which alpha6beta4 signaling promotes prostate cancer progression in vivo. Molecular and cellular techniques will be used to compare prostate tumor invasion and angiogenesis in TRAMP mice and PTEN-conditional null mice (PTENPC) mice carrying either wild type or mutant beta4. We will also evaluate the effect of androgen ablation in both models. 2) To examine the cellular mechanism by which beta4 signaling promotes prostate cancer progression. Prostate carcinoma cell lines will be isolated from TRAMP or PTENPC mice expressing wild type or mutant beta4. In vitro and in vivo assays will be used to compare their ability to proliferate, to resist apoptosis, to organize pseudoacini in Matrigel, and to migrate/invade. 3) To examine the molecular mechanism by which beta4 signaling promotes prostate cancer progression. Signaling methods will be used to compare the activation of various beta4 pathways in prostate cancer cells expressing wild type or mutant beta4. Reconstitution of beta4 knock-down cells with either wild type beta4 or various signaling-defective mutants will enable us to identify the major signaling pathways through which alpha6beta4 controls the malignant phenotype in prostate cancer. 4) To examine the validity of alpha6beta4 as a target for anti-tumor therapy. We will study the expression of alpha6beta4 during human prostate cancer progression and test the effect of beta4 signaling-inhibitory antibodies in xenograft models.
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