Elucidating the Role of the Disintegrin Metalloproteinase, ADAM15, in Breast and Prostate Cancer Progression.

The metastatic progression of cancer requires multiple steps involving tumor cell stromal interaction, which has been demonstrated to be supported by the matrix metalloproteineases (MMPs). The ADAMs (a disintegrin and metalloproteinase) are a recently discovered family of proteases related to the MMPs. These zinc-dependent metalloproteinases are involved in a myriad of normal and pathophysiological functions including oocyte fertilization, neurogenesis, inflammation and cancer progression. The domain structure of ADAM family members implicate these enzymes in multiple functions such as cell adhesion, migration, invasion, and signal transduction. A catalytically active member of the ADAM family, ADAM15, has been shown to be upregulated in multiple adenocarcinomas including breast and prostate cancer. It is thought that ADAM15 plays a role in growth factor shedding to mediate cancer cell migration and invasion through its metalloproteinase activity. The ADAM15 disintegrin domain supports microenvironment modulation by mediating extracellular matrix degradation and angiogenesis. In this thesis work, I demonstrate that ADAM15 supports prostate cancer tumorigenesis and metastasis through the regulation of metastatic associated markers. More importantly and for the first time, ADAM15 was implicated in soluble E-cadherin (sEcad) ectodomain shedding. The sE-cad fragment bound and activated ErbB receptors leading to breast and prostate cancer cell migration, proliferation and survival.PhDCellular & Molecular BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/60853/1/abdonajy_1.pd