Obesity has been clearly established as an important risk and prognostic factor for several types of cancer, particularly breast cancer, but the role of obesity in lung cancer remains controversial and requires clarification. Inverse associations between body mass index (BMI) and lung cancer risk have been reported (1, 2). However, these might be due to residual confounding by smoking. Also, several epidemiological studies that focused on dietary factors instead of BMI have shown positive associations between high dietary fat intake and lung cancer risk and mortality (3-6). One potential mechanism by which obesity enhances breast cancer risk involves altered estrogen metabolism through increased aromatase activity and altered estrogen receptor signaling mediated through the inflammatory mediator nuclear factor kappa-B (NF-:B) (7). Whether a similar mechanism occurs in the lung has not yet been investigated, but the role of estrogen signaling in the development and progression of lung cancer is now firmly established. Lung tumors express estrogen receptors and aromatase with no sex difference in expression (8). High expression of these markers in lung tumors has also been correlated with poor prognosis in lung cancer patients. Furthermore, several large cohort studies have implicated the estrogen pathway in lung tumorigenesis and have demonstrated a protective effect of anti-estrogen therapy in the prevention of lung cancer (9,10). We have recently shown that the aromatase inhibitor anastrozole can inhibit tobacco-induced lung tumorigenesis in mice and that hormonal signaling markers are expressed in pulmonary inflammatory cells infiltrating murine preneoplasias and tumors in this model system, suggesting that the inflammation-aromatase link also exists in lung cancer. In addition, combined inhibition of estrogen and inflammatory pathways results in enhanced anti-tumor effects in the lungs of mice, confirming the link between these two pathways. Thus, the inflammation-estrogen signaling axis may underlie the link between obesity and lung cancer risk as well. Given these findings, we hypothesize that obesity contributes to lung cancer risk by increasing both inflammation in the lung and release of estrogen. The goal of this proposal is to elucidate the mechanistic link between obesity, inflammation and estrogen signaling in lung carcinogenesis and thereby advance our understanding of the molecular mechanisms by which obesity affects lung cancer risk. This hypothesis will be addressed using a preclinical animal model as well as a population study in the experiments of the following Specific Aims: 1) Determine the role of diet-induced obesity in promoting lung carcinogenesis caused by tobacco carcinogen exposure and the ability of estrogen pathway inhibitors and/or inflammatory inhibitors to reduce this effect; and 2) Determine the relationship between markers of inflammation and/or obesity as well as circulating hormone levels and lung cancer risk. Should this exploratory study reveal that obesity related factors are linked to the estrogen and/or inflammatory signaling pathways that play a role in lung tumorigenesis, strategies involving hormonal manipulation and/or anti-inflammatory therapies in select high-risk populations may be beneficial for lung cancer prevention.
Lung cancer kills more Americans every year than any other type of cancer. Lung cancer is typically diagnosed at a late stage and does not respond well to current treatments. Early detection of lung cancer has not been successful as symptoms often do not appear until the disease is advanced. The five-year survival rate for all stages of lung cancer combined is only 15%. This statistic suggests that a viable strategy for reducing lung cancer mortality is through prevention. This exploratory study will investigate whether or not obesity related factors play a role in lung cancer risk by increasing inflammation in the lung and release of estrogen. These studies will elucidate if a mechanistic link between obesity and estrogen signaling exists in early lung cancer which may lead to novel lung cancer prevention strategies.
