A major problem in cancer management is metastasis - contributed to by the recurrent migration and invasion of tumor cells in the vasculature and tissue parenchyma which parenchyma which perpetuate tumors at multiple locations in the body. Of the many types of cancers facing diagnosis and treatment breast carcinoma has been increasing at an alarming rate in the United States over the past two decades. From a clinical point of view, early detection of breast carcinoma determines diseases prognosis. Unfortunately, there is good evidence to suggest that at the time of diagnosis, a high proportion of patients already have occult or clinically detectable metastasis. Thus, there is a dire need to identify additional prognostic markers for disease progression. This proposal seeks support to study a novel mammary associated gene - called maspin (mammary serine protease inhibitor), which has tremendous diagnostic as well as therapeutic value. However, the biological mechanism(s) of action governing its function(s) remain enigmatic.
Aim 1 : To investigate the molecular mechanisms(s) that mediate maspin inhibition of breast cancer cell motility (including migration an invasion).
This aim will examine the nature of maspin function with respect to the regulation of pericellular proteolysis and interrelatedintegrin/uPAR function - which are critical components of tumor cell invasion of ECMs (extracellular matrices). Hypothesis; Maspin affects breast cancer cell migratory and invasive activity by inhibiting the extracellular proteolysis of EMC components which is regulated by an integrin- mediated event involving uPAR.
Aim 2 : To characterize the intracellular signaling intermediates that are involved in the integrin/uPAR-mediated response to maspin.
This aim will allow us to elucidate our most recent observations regarding the role of the cytoskeleton with respect to change(s) in cell shape and locomotion - coordinated events in cell migration - in response to maspin. Hypothesis: Maspin inhibits cell motility by altering integrin-mediated attachment to specific ECM components - which consequently affects cell shape and locomotion.
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