Latent Transforming Growth Factor-? (TGF-?) Binding Protein (LTBP) is bound to TGF-P and is essential in most cells for its proper folding and secretion. In addition, LTBP localizes TGF-? to the extracellular matrix and helps maintain its latency until activated. TGF-? has many functions that have relevance to breast cancer, including growth inhibition, regulation of apoptosis, maintenance of stem cell quiescence, promotion of epithelial-to-mesenchymal transition, and extracellular matrix deposition during radiation-induced-fibrosis. There are three TGF-?s, all of which are expressed in the breast, and though they share the same receptors, they have distinct in vivo functions. In addition, there are three different LTBPs that can bind TGF- ?, but nothing is known about the function of these proteins the in the mammary gland. Given the significance of TGF-? to both inhibition of tumor development and promotion of breast tumor metastasis, and LTBP's role as a regulator of TGF-?, this proposal aims to determine the effects of loss of LTBP function on TGF-? activation and murine models of breast cancer. Due to lack of knowledge about LTBPs in breast and established links between misregulation of developmental processes and cancer development, I also propose to determine LTBP expression and loss-of-function effects during murine models of breast development. Relevance TGF-? is intimately linked to breast cancer in several ways: in early stage cancers, it inhibits cells from proliferating, providing protection from tumor progression;in late stage cancers, it promotes metastasis of tumor cells;it also contributes to fibrosis experienced after radiation treatment. LTBPs regulate TGF-? in other tissues, but nothing is known about their function in the breast. This project aims to understand LTBP expression and functions during breast development and cancer.
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