Breast cancer is the most common malignancy in US women. Approximately 90 percent of patients dying with breast cancer have skeletal metastases. These mestastatic lesions cause devastating complications including intractable bone pain, pathological fractures and hypercalcemia. Thus, bone metastasis is one the major cause of increased morbidity and eventually mortality in breast cancer patients. Nevertheless, the mechanisms by which breast cancer colonizes the skeleton are still poorly understood. Bone stores a variety of growth factors that are released into the bone microenvironment as a consequence of bone resorption. Insulin-like growth factors (IGFs) are the most abundant of the growth factors that are present in bone. Several clinical studies have demonstrated that IGF type I receptor (IGFIR) expression is elevated in malignant breast tumors compared with that in normal breast tissue, and many workers have shown that IGFs stimulate proliferation of cultured human breast cancer cells. We have, therefore, developed a hypothesis that bone-derived IGFs are responsible, at least in major part, for stimulating human breast cancer cell proliferation in the bone microenvironment. An additional goal is to study for the IGFIR downstream signaling pathways which may play a role in bone metastasis of breast cancer. We will focus on the transcription factor NF-kappaB, since it has been shown that IGF-I activates the NF-kappaB and constitutive activation of NF-kappaB has been found to be associated with the progression of metastatic growth of human breast cancer cells.
Our Specific Aims are 1. to determine if IGFs released from bone during increased bone resorption accelerates local bone metastasis and proliferation of human breast cancer cells in bone using neutralizing antibodies to IGFIR 2. to examine the effects of stable overexpression of the wild-type IGFIR on the capacity of human breast cancer cells to cause bone metastases 3. to determine the capacity of human breast cancer cells stably overexpressing mutated dominant-negative IGFIR to develop bone metastases 4. to study the role of NF-kappaB in bone metastasis using mutant forms of Ikappa-B which inhibits NF-kappaB activation 5. to examine the effects of antisense oligodeoxynucleotides (ODN) to IGFIR and NF-kappaB on bone metastasis
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