The ability of the mammary gland to undergo tumorigenesis is influenced by its normal development, including reproductive events. Numerous epidemiological studies have suggested that systemic endocrine patterns and reproductive changes occurring in the human breast have important implications for breast cancer. The observation that the same endocrine events control mammary development and influence breast-cancer risk strengthens the hypothesis that mammary gland development and tumorigenesis are fundamentally linked. Understanding the mechanisms by which these events regulate breast cancer development will require a better understanding of the genes that control mammary cell proliferation and metastasis. Protein kinases are the largest class of genes known to regulate growth, differentiation, and development in eukaryotic organisms. We propose here to investigate the influence of p21-activated kinase (Paki), a serine/threonine kinase (with roles in motility, invasiveness, angio genesis, and cell survival), on the development of the normal mammary gland and alterations involved in early malignant and metastatic breast cancer. Our working hypotheses are that functional Pak1 pathway is required for normal mammary gland development and that deregulation of the Pak1 signaling pathway plays an essential role in the progression and maintenance of flu invasive phenotype in breast cancer by supporting cell survival and angiogenesis. The rationale for this proposal is based on observations recently made by the Principal Investigator that (i) expression of Pak1 controls motility, invasiveness and anchorage-independent growth of breast cancer cells; (ii) Pak 1 signaling regulates the expression of vascular endothelial growth factor and consequently its function; (iii) Pak1 activation supports cell survival by inactivating the proapoptotic protein Bad; and (v) conditional expression of a kinase-dead Paki in a transgenic mouse model leads to hypoplasia, retardation of ductal structures, and enhancement of intraductal stroma. These findings suggest that Pakl has a significant role in normal mammary development by controlling several essential functions, including cell motility and remodeling, angiogenesis, and cell survival. Thus dysfunctions in the Pakl pathwa3 may constitute an important step in breast cancer development.
The Specific Aims of this proposal are to: (1) determine the influence of expression of dominant-negative Pakl in the mammary gland of transgenic mice; (2) determine the influence of constitutively active Paki on mammary gland biology in transgenic mice; (3) determine whether co-expression of Pakl can influence mammary gland tumorigenesis in HRG transgenic mice; and (4) determine the influence of Pak1 functions on the susceptibility. A unique aspect of our proposal is the use of recently developed Pak1 transgenic mice to gain novel insights about the role of Paki as critical signaling pathway in normal mammary gland development, and will also allow the Principal Investigator to validate the previous tissue culture findings in the pathophysiologically relevant experimental setting by using whole animals.
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