Breast cancer is the number one form of cancer and the second leading cause of cancer deaths among US women (18). Of the known breast cancer risk factors (age, sex, family history, diet), only diet may be controllable (11). The "dietary fat/breast cancer" hypothesis, however, is controversial (22). Despite this controversy national health agencies recommend a reduction in fat intake to reduce breast cancer risk and clinical trials with very low fat diets are in progress with high risk women and breast cancer patients (28). In addition, the historic Women's Health Initiative will soon test the "dietary fat/breast cancer" hypothesis with a 10 year study enrolling 70,000 women (16,26). Much of the controversy over the role of dietary fat in breast cancer stems from the lack of a biochemical mechanism linking fat and tumor promotion. CCAAT/Enhancer binding proteins (C/EBPs) are transcription factors implicated in the regulation of genes involved in growth control, differentiation and energy metabolism (1-15). These unique properties have led to speculation that C/EBP isoforms may play a general role be tumorigenesis and may play a specific role as a link between dietary fat and mammary tumor promotion. Mammary gland expresses a unique pattern of C/EBP isoforms suggesting important functions for C/EBPs in normal mammary gland biology. This proposal will investigate the expression of C/EBP isoforms during mammary gland proliferation and assess the potential role of C/EBPs in mammary tumor promotion by dietary fat. Three specific objectives are proposed. (1) Investigate C/EBP isoform mRNA levels during three principal proliferative phases in normal mouse mammary gland development: embryonic, sexual maturation and during pregnancy/lactation. (2) Investigate the influence of varying corn oil (CO) intake [5, 12.5 and 25% CO (by calorie)] on mammary gland C/EBP isoform expression in normal mouse mammary gland and in mammary tumors developed in transgenic mice (MMTV/c-neu) (51). (3) Investigate the influence of proliferation and differentiation of mammary cells on C/EBP phosphorylation and nuclear localization. Current public health information regarding breast cancer is limited to encouraging early detection of existing disease. It is imperative that we investigate the regulation of genes, such as C/EBPs, that are implicated in mammary cell growth control, differentiation and possibly tumorigenesis. In addition, C/EBP isoforms may provide a biochemical link between dietary fat and mammary tumorigenesis. Understanding this link could lead to the implementation of effective preventative measures to reduce breast cancer risk.
NIH ExPorter
NIH ExPorter