): The candidate's research experience is in the field of bone cell biology, where her main interests have been in growth factors, extracellular matrix proteins and myeloma bone disease. The candidate is at the end of her postdoctoral training and wishes to become an independent investigator, capable of directing high quality academic research in her own laboratory. To do this, she proposes to being her expertise in bone matrix and growth factors into the field of breast cancer. Breast cancer frequently metastasizes to bone and often causes bone destruction, with debilitating complications for the patient. The proposed studies are based on the hypothesis that bone matrix-bound growth factors play a key role in defining bone as a fertile ground for the growth of breast cancer cells. These studies define an area of interest for the candidate which is separate from that of her mentors, but allows her to draw from the expertise she has gained from her postdoctoral training. The candidate would obtain additional training during years 1 and 2 from her co-sponsors, Drs. Theresa Guise and Lynda Bonewald, to prepare her for entry into the field of breast cancer as a productive researcher. By year 3 the candidate will be a fully independent investigator. The candidate is currently in the Division of Endocrinology, which has a large group of workers who are experts in the field of breast cancer. Thus there will be many opportunities for professional interactions with senior colleagues, and for presentation and discussion of data. The candidate would also become a member of the San Antonio Cancer Institute and benefit from the resources provided by this organization. The goal of the proposed studies is to examine the role of bone matrix-bound transforming growth factor beta (TGFbeta) in regulating the bone destructive capacity of metastatic breast cancer cells through stimulating production of parathyroid hormone related protein (PTHrP), a powerful bone resorbing factor.
Specific Aim 1 will examine whether bone matrix-derived TGFbeta is responsible for stimulating PTHrP production by breast cancer cells, thereby increasing cancer-associated bone destruction. This will be done using in vitro and in vivo models.
Specific Aims 2 and 3 will examine the molecular mechanisms for release of bone matrix-bound TGFbeta by breast cancer cells. Initially it will be determined whether release occurs through proteolytic cleavage of the latent TGFbeta binding protein (LTBP-1) as is the case with bone cells. The proteolytic cleavage sites in LTBP1 will then be mapped and antagonist peptides designed to inhibit cleavage of LTBP1 and the resulting release of TGFbeta from bone matrix.
Specific Aim 4 will examine the ability of breast cancer cells to activate matrix-released latent TGFbeta. This study will provide a new approach for studying the complex interactions between breast cancer cells and the bone microenvironment and may lead to the development of new therapies to reduce cancer-associated bone destruction.
