The Fuchs-Young laboratory studies the basic mechanisms of breast carcinogenesis, including the interaction (cross-talk) between the estrogen receptor alpha (ERa), IGF-1 and p53 signaling cascades. Our research utilizes a variety of unique in vivo and in vitro models, including transgenic and humanized mice. An underlying theme of our research is the discovery of bio-physiological determinants of disparities in breast cancer incidence and outcome.
One of our projects utilizes the BK5.IGF-1 transgenic mouse model, in which IGF-1 expression is directed to the K5+ myoepithelial cells, and thus mimics the paracrine effects of stromal IGF-1 on mammary ductal epithlelium. This is one of the few mammary cancer models in which tumors express functional estrogen receptor, and it is therefore a useful model for studying cross talk between the ER and IGF-1 signaling systems. Studies with this model have identified a developmentally controlled “pathway switch” that determines the effects of IGF-1 on mammary development and tumor susceptibility. These results have implications for human breast cancer, and suggest that elevated tissue levels, in addition to circulating levels of IGF-1, are critical in determining tumorigenesis and that early, prepubertal exposures maybe important in mediating lifetime susceptibility.
Another project focuses on the interdependent regulation of ER and p53, and the role of racially disproportionate p53 polymorphisms in mediating breast cancer development and progression. Our studies have revealed that p53 regulates ER expression at both the message and the protein levels. These results provide insight into one of the mechanisms by which ER–/p53 null tumors develop, and indicate that expression of ERa in tumors, an important indicator of prognosis and response to therapy, is determined by when and if p53 is lost during tumorigenesis. Studies of racially disproportionate p53 polymorphisms utilize a novel, “humanized” mouse model. These investigations are focused on evaluating the role of these variants in mediating reduced pregnancy protection, and increased risk of aggressive, premenopausal cancers with poor prognosis, in women of color.
A new project in the laboratory project is focused on investigating the impact of exposure to metabolic syndrome during different stages of development on metabolic function and mammary cancer risk. This line of research was initiated, in part, due to the obesity epidemic in the US, and the increasing prevalence of obesity in younger children. Initial results show that manipulation of gestational, lactational and post-weaning diet can have very significant effects on susceptibility to mammary carcinogenesis.