Women in the United States have among the highest breast cancer rates in the world. This is not due to increased genetic susceptibility, as less than ten percent of breast cancers are attributed to gene mutations such as BRCA1. This observation suggests that environmental factors including nutrition and lifestyle may be major contributors for the tumorigenic process. We have developed a rat model to examine tumor progression and to identify risk factors which develop during puberty and/or during gestation as a result of environmental insults. Specifically we have explored the effects of dietary fatty acids including olive, or safflower oil or butter fat on tumor progression. When rats were exposed to these dietary agents during gestation, and throughout their lifespan (110 days), a significant increase in mammary tumor progression compared to the AIN control diet were observed when a single low dose of DMBA was administered at 21 days. There was an increase in average tumor volume per animal and the progression of CIS to invasive tumors. A significant feature of this model is the range in size of the CIS lesions. Also, the number of invasive tumor was relatively small, which is similar to the human progression of CIS lesions to invasive tumors. We have collected invasive tumors, and large and small CIS lesions for microarray expression analysis. The dietary agents (olive oil and butter fat) were clearly acting as tumor promoters in this model. We examined the effects of these dietary agents on epithelial cells during mammary gland development in the puberty phase. It was clear that these agents not only increased the ongoing cell proliferation during puberty, but also activated the checkpoint pathways suggesting that the exposures to these diets are causing DNA damage. This is one aspect of the tumor promotional properties of these dietary agents. Another study is related to epigenetic changes that may occur during gestation when the dams are exposed to these dietary agents. If epigenetic changes are observed in the pups compared to the AIN diet, then we will determine if these changes predispose these pups to tumorigenesis when a small dose of DMBA is administered during puberty or later in life. This model could be used to examine the effect of various environmental insults on mammary tumorigenesis in young pups or mature animals and mechanisms of tumor progression can also be examined.
Grant: ES012770