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Mechanisms of aberrant growth signaling in a rat model of early-onset breast cancer
RISK and Prevention, Epidemiology
Dr. S E Ozanne, U. Cambridge , U.K. Background :Insulin resistance, type-2 diabetes and low and high birth weight are risk factors for breast cancer. We have found that low birth weight, insulin resistance and increased early mammary tumor incidence are reproduced by the manipulation of maternal diet in our rat model. The molecular basis of the increased tumor susceptibility is not yet understood. It may be associated with raised insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R) protein levels in offspring mammary glands which accompany rapid growth of the glands post-weaning. Both preferential IR-isoform A and raised IGF-1R levels are associated with increased mitogenic signaling and breast cancers. IGF-1R transcription is controlled by the tumor suppressor genes BRCA1, p53 and WT-1. The fetal environment may modulate the activity of these factors resulting in increased IGF-1R transcription and protein expression. Secondary factors such as obesity, which increases insulin, IGF-1 and sex hormone levels, could activate mitogenic signaling in cells with a higher density of IR and IGF-1R, further increasing tumor potential. Hypothesis: A poor fetal environment increases breast cancer risk by increasing mammary expression of IR and IGF-1R. Adult obesity-driven hyperinsulinemia increases insulin/IGF-1 signaling to further increase risk. Objectives: To dissect the potential molecular mechanisms by which poor early growth leads to increased risk of breast cancer and determine the metabolic factors influenced by adult obesity to increase breast cancer risk. Specific Aims: To examine known regulators of IGF-1R, quantify key insulin and insulin-like signaling molecules and establish if hyperinsulinemia further increases risk in low birth weight (LBW) rats. Study design: (1)Take cleared mammary fat pads from control and LBW offspring (n=8 for each age groups: 3, 4, 5 and 7 weeks) to determine (i) mRNA expression of BRCA1, p53, WT-1, Sp-1 and IR isoforms (ii) tissue IGF-2, IR-IGF-1R hybrid protein expression; (2)Induce obesity to study mammary tumor susceptibility and study possible mechanisms involved. Potential Outcomes and Benefits: This project is highly relevant to women of low birth weight. It will investigate the possible mechanisms of rapid growth and the interactions between metabolic disorders and breast cancer with the prospect of suggestions for suitable preventative or therapeutic intervention.
Dr. S E Ozanne, U. Cambridge , U.K. Background: Type-2 diabetics have an increased breast cancer risk. Type-2 diabetes is associated with low birth weight. Both low and high birth weight extremes are risk factors for breast cancer, suggesting that the fetal environment is important to the way breast tissue develops. Elevated pregnancy estrogen levels have been hypothesized as one factor conveying this risk. Our studies are based on a rat model of intrauterine under nutrition which results in low birth weight offspring. These offspring later develop high insulin concentrations, insulin resistance and diabetes, which we hypothesize, is the intermediate causal link between low birth weight and breast cancer. We therefore asked if estrogen concentrations were raised in the mother’s blood during pregnancy in this model and found that it was. We also checked if offspring mammary tissue was subsequently altered and found that postnatal development was retarded but rapid growth ensued within one week of weaning onto a normal diet. We have shown that this is associated with and possibly due to a capacity to over-respond to insulin and a related growth factor, a further link with breast cancer. This feature may be influenced by high insulin levels of the diabetic state resulting in uncontrolled proliferation and disease. We recently determined if these rats were more susceptible to chemically-induced mammary tumors and found they developed twice as many early tumors than normal rats. Objective/Hypothesis: Poor intrauterine growth alters normal breast growth to increase breast cancer risk. We will study the mechanisms of this increase, what indicators predict risk and how to attempt prevention/treatment of this route to breast cancer. Specific Aims: 1. To study the profile of molecules regulating breast development in early life. 2. To determine if obesity, which drives the diabetic state, further enhances mammary tumor development. Study design: Collect mammary glands of offspring at 3, 4, 5 and 7 weeks age to study insulin and related growth signaling components.Investigate tumor potential in obese low birth weight rats. Potential Outcomes and Benefits: This research will give us critical information as to whether certain tumor suppressor genes are altered by a poor fetal environment and how they act to increase an individual’s breast cancer risk. It will also compliment the tailored therapy approach based on a patients’ own genetic or metabolic profile.