Sex differences in chemically induced lung cancer and epigenetic mechanisms

Epidemiological studies have indicated that females are at increased risk of lung cancer compared to males. Different experimental studies have supported the hypothesis about sex differences in lung cancer biology. Our data indicate that females show increased susceptibility to PAH which is associated with increased expression of the CYP1A1 gene that is important in bioactivation of PAH. It is assumed that steroid receptors may be involved in these sex differences. Forkhead box A (FOXA)-factors regulate the activity of estrogen and androgen receptors and are important for cancer development in hormone dependent tissues like breast and prostate. To what degree these factors are involved in lung cancer is not known. Our hypothesis is that FOXA factors may be involved in lung carcinogenesis and that they can play a role in sex differences in the risk of lung cancer.
A new and important field in toxicology is epigenetics which deals with the regulation of genes and the environmental impact. Epigenetic changes are strongly associated with environmental exposures. In this project we will study epigenetic markers such as DNA methylation, expression of micro-RNA, and histone modifications.
The main objectives of this project are to characterize mechanisms behind sex differences in risk of chemically induced lung cancer and to generate increased knowledge about the role of epigenetic mechanisms. The project is organized into two major parts: (1) By using samples from STAMI’s lung cancer biobank, we study if differences in expression of the FOXA1 and FOXA2 genes in normal and cancerous lung tissue can be explained by gene copy number variation (FOXA1) and DNA methylation (FOXA2), respectively. (2) We have obtained lung cells with cancer-like properties (so-called transformed cells) after long-term exposure of normal lung cells to PAH or to a condensate of cigarette smoke. These new cell lines are characterized for differences in cell biology and molecular markers. We have found that the transformed lung cell lines show significantly reduced expression of both FOXA genes. We study if reduced expression of FOXA2 can be explained by altered DNA methylation similarly to what is found in lung tumors. The impact of altered expression of the FOXA genes on PAH bioactivation genes like CYP1A1 and CYP1B1 is also studied, together with analysis of associations between altered expression of micro-RNA and appearance of transformed phenotype