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Identification of the critical RANKL sheddase and the role of RANKL in breast cancer and metastasis


Diseases associated with bone loss, cancer, and bone metastases affect millions of people andresult in severe disabilities, pain, and premature death. The group of Prof. Penninger was the first togenetically show that the TNF-family molecule RANKL (OPGL, T RANCE, ODF) and its receptorRANK are key regulators of bone remodeling (Kong et al Nature 1999). RANKL and RANK areessential for the development and activation of osteoclasts and bone loss in response to virtually alltriggers tested. Inhibition of RANKL fu nction via the natural decoy receptor osteoprotegerin preventsbone loss in postmenopausal osteoporosis, arthitis, and infection-induced tooth loss. RANKL andRANK are also essential for the morphogenesis of a lactating mammary gland, which provided anevolut ionary rationale for hormonal regulation of osteoporosis (Fata et al., Cell 2000). SinceRANK/RANKL control calcifications, a hallmark of mammography screening for breast tumors, andclassical breast cancer pathways such as NFkB and CyclinDl are activated by RANKL, we proposethat RANKL-RANK have a role in breast cancer and metastasis of epithelial tumors. Preliminaryresults suggest that RANKL plays an essential role in the cell migration of epithelial tumor cells intobones and in vivo inhibition of RANKL/RANK signaling results in a marked reduction in tumor burdenin bones, but not other tissues. Tomoki Nakashima has recently found that membrane-anchoredRANKL works more efficiently than the soluble RANKL in in vitro osteoclastogenesis assays(Nakashima et al; 20 00). The essential enzyme that controls RANKL shedding and thus the biologicalactivities of RANKL has not been identified yet.We propose experiments 1. to identify specific molecules that control the shedding of membrane boundRANKL to soluble RANKL and gen etically validate the functions of these molecules in vivo and 2. toidentify the essential RANKL in breast cancer and cancer metastases.Identifi#

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