Alcohol, obesity, and estrogen regulate mammary tumorigenesis through adiposity and the PI3K/Akt signaling pathway
Breast cancer is the most common cancer and the second leading cause of cancer deaths among women in the United States. Alcohol consumption increases breast cancer risk in women. It is unclear whether the effects of alcohol on mammary tumorigenesis are modified by body weight or exogenous estrogen. To determine if the effects of alcohol on mammary tumors are modified by body weight, mice of different body weights (lean, overweight, obese) consuming water or alcohol were injected subcutaneously with mammary cancer cells. To determine if the effects of alcohol on mammary tumors are modified by estrogen, pellets delivering estrogen were implanted into female mice, followed by subcutaneous mammary cancer cell injections. Results show that alcohol-consuming mice were more insulin sensitive and developed larger tumors sooner than water-consuming mice (p<0.05). Our data show obese mice developed larger tumors than lean mice. Exogenous estrogen triggered the loss of body fat, induced insulin sensitivity, and suppressed tumor growth. Obese mice had higher levels of insulin, IGF-1, leptin, and VEGF. The only mammary tumor growth factors increased by alcohol consumption were leptin and VEGF (p<0.05). In addition, activation of the PI3K/Akt signaling pathway was induced by alcohol and obesity in mammary tumors. Furthermore, alcohol increased the invasiveness of breast cancer cells in a dose-dependent manner, but also decreased a metastasis suppressor gene Nm23. Collectively, my dissertation suggests that alcohol consumption, obesity, and estrogen treatment regulate mammary tumorigenesis through hormones associated with adipose tissues and the PI3K/Akt signaling.