Breast cancer is the most common malignancy among women in Western countries. However, despite significant efforts to develop valid predictors of breast cancer metastatic potential, there remains a critical gap in our understanding of the molecular function(s) of the genes involved in the maintenance of the normal mammary epithelial phenotype, many of which are altered during the onset and progression of breast cancer. This competitive renewal application advances our knowledge of the biological function(s) of maspin (mammary serpin) and its interactions with a newly identified binding partner IRF6 (Interferon Regulatory Factor 6) -- and focuses on characterizing their independent and collective mechanistic role(s) during normal mammary gland acini development and their loss during breast cancer progression, using the following experimental strategy:
Specific Aim 1 : Explore the relationship between maspin and IRF6 related to the acquisition and maintenance of the normal mammary epithelial cell phenotype and suppression of the breast cancer cell phenotype, using loss-and-gain-of-function experimental strategies. Hypothesis: Maspin and IRF6 work in an integral manner as suppressors of migration, invasion, tumorigenesis and/or metastasis.
Specific Aim 2 : Determine the cellular and molecular effects of maspin/IRF6 interactions on the deposition of maspin protein into the extracellular microenvironment by normal mammary epithelial cells, and on potential phenotypic changes in breast cancer cells exposed to it, using three-dimensional culture models. Hypothesis: Maspin/IRF6 interactions result in the secretion and deposition of maspin protein into the microenvironment by normal mammary epithelial cells which can influence an epigenetic change in the phenotype and biological activity of breast cancer cells.
Specific Aim 3 : Examine the differential effects of maspin and IRF6 re-expression on breast cancer cell interactions with their extracellular microenvironment, with particular focus on the cleavage of laminin 5 gamma2 chain by matrix metalloproteinases into promigratory fragments. Hypothesis: Re-expression of maspin and IRF6 in breast cancer cells diminishes the production of laminin 5 gamma2 and matrix metalloproteinases by breast cancer cells, resulting in their inability to cleave laminin 5 gamma2 chain into promigratory fragments. The translational value of these studies rests in the development of new strategies to re-express tumor suppressors in breast cancer cells that result in the neutralization of differentiation and promigratory signals in the microenvironment.
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