UCSF

This thesis work endeavors to determine the role of a minor protease of the contact activation system, plasma kallikrein, in the complex process of involution of the mammary gland. Previously, it was determined that plasma kallikrein (PKal) could activate plasminogen (Miles et al., 1983) and was the predominant plasminogen activator in the differentiation of adipocytes both in vitro and in the mammary gland (Selvarajan et al., 2001). My work took up this thread of inquiry to pursue resultant questions: 1) Does specific inhibition of PKal inhibit adipocyte replenishment in mammary gland involution? 2) How is PKal activity regulated in the mammary gland? 3) Does a genetic knockout approach phenocopy the effects of in vivo inhibition of PKal in the mammary gland?

Thus, Chapter One provides background firstly on plasminogen and the mammary gland, prekallikrein and PKal, and secondly, on mast cells, intriguing protease porting immune cells. Chapter Two details the effort to produce a prekallikrein-deficient (PKal knockout) mouse. Next, Chapter Three describes results of in vivo inhibition of PKal during mammary gland involution. Chapter Four describes the localization of PKal in the mammary gland and analysis of its expression. Chapter Five addresses the question of the role of mast cells in mammary gland involution through analysis of genetic and chemical models of mice without or with altered mast cells. This thesis posits PKal as an important target of future research into its role in other physiological systems as well as in breast cancer progression and metastasis. This thesis also reveals mast cells as a novel participant in mammary gland development.