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A Novel Mouse Model to Study Endocrine Effects of IGF-1 in Breast Cancer
Background: While abundant evidence exists for autocrine/paracrine action of IGF-I in breast cancer, little is known about the role of circulating IGF-I. Studies have shown that circulating IGF-I levels can predict breast cancer risk, and mammographic density is strongly related to both circulating IGF-I levels and breast cancer risk. Furthermore, circulating IGF-II may regulate stem/progenitor cell number, and, therefore, IGF levels might be associated with increased cancer risk perhaps due to an increased chance of developing or propagating mutations in stem/progenitor cells. Objective/Hypothesis: I therefore hypothesize that circulating IGF-I can reach and stimulate the normal mammary gland, and that this will increase stem/progenitor cell number and increase tumorigenesis in a mouse that has a predisposing oncogene. Additionally, I hypothesize that reduction of circulating IGF-I levels will prevent or delay breast cancer. Specific Aims: 1. Assess the effect of increased systemic IGF-I on mammary stem/progenitors cell number, and cancer incidence and progression. 2. Can lowering of circulating IGF-I, by the growth hormone antagonist pegvisomant, prevent or delay mammary tumorigenesis? Study Design: To directly and mechanistically test my hypothesis I will use our newly developed liv-IGF-I liver transgenic mouse model, the first mouse model that overexpresses IGF-I in the liver resulting in increased systemic levels of IGF-I. I will test whether increased systemic IGF-I promotes mammary tumorigenesis using MMTV-ErbB2 and MMTV-IRS transgenic mice, if this is mediated via IGF-IR, and the affect this has on mammary stem/progenitor cell number and function. I will then test whether neutralization of IGF-I with a growth hormone antagonist, pegvisomant, can block the actions of circulating IGF-I and prevent or delay mammary tumorigenesis. Relevance: Recent evidence indicates that individuals with IGF-I levels at the higher end of the normal range show increased risk of breast cancer. A better understanding of IGFs endocrine action in breast cancer may lead to the development of new and better therapies to reduce breast cancer incidence and increase survival by lowering serum IGF-I levels. The novel mouse model that we will use will be a critical resource not only for testing the effects of circulating IGF-I, but may also serve as a tool for examining the effects of IGF-IR inhibitors in breast cancer.
Growth hormone (GH) secreted from the brain is fundamental to growth and development in humans and in animals. One way GH controls overall growth is by causing the release of insulin-like growth factor-I (IGF-I). IGF-I has the characteristics of both a circulating hormone and a tissue growth factor. IGF-I is produced in numerous organs and tissues throughout the body, however, most IGF-I found in the circulation is produced and released by the liver. Although it is known that circulating levels of IGF-I vary with in a normal population, recent evidence indicates that individuals with IGF-I levels at the higher end of the normal range show increased risk of breast cancer. In addition, mammographic density is strongly related to both circulating IGF-I levels and breast cancer risk. Although the relative risks are modest, this risk could apply to approximately 25% of the population which have high levels of circulating IGF-I, thus the causative disease burden might be substantial. In the following proposal we will be the first to use a newly developed mouse model that has increased production and release of IGF-I from the liver to examine the effects circulating IGF-I has on breast cancer development and growth. This model in combinations with other mice models known to have breast cancer, will allow us to be the first to provide mechanistic evidence supporting that increased circulating levels of IGF-I do in fact dictate breast cancer risk. We predict that circulating levels of IGF-I from the liver will be able to reach and excite the normal mammary gland, through an alteration in stem/progenitor cell numbers and that this will increase tumor formation. In addition, we believe that by blocking systemic IGF-I, we will block the effect of circulating IGF-I to reduce stem cell number and prevent or delay breast cancer. Understanding how critical a role the endocrine action of IGF-I is in tumor development could be a critical step towards the eventual prevention or delay of breast cancer. Given that serum IGF-I levels are a strong risk factor for breast cancer, and that IGFs have an important role in both normal breast development and breast cancer growth, IGFs may be an ideal target for breast cancer prevention.