Liver X receptors and estrogen receptor ß, two players in a rare subtype of NSCLC.

ABSTRACT

Liver X receptors (LXRαß) play essential roles in the maintenance of the normal functions of macrophages, in modulation of immune system responses and cholesterol homeostasis. We have reported that LXRαß-/- mice develop squamous cell lung cancer. We now report that those LXRαß-/- mice, which live to 18-months of age, spontaneously develop a second type of lung cancer resembling a rare subtype of NSCLC (TTF-1 and P63-positive). The lesions are characterized as follows a high proliferation rate; a marked accumulation of abnormal macrophages; an increase in the number of regulatory T cells; a remarkably low level of CD8+ cytotoxic T lymphocytes; enhanced TGFß signaling; an increased expression of matrix metalloproteinases accompanied by degradation of lung collagen; and a loss of estrogen receptor ß (ERß). Because NSCLC is associated with cigarette smoking, we investigated the possible links between loss of LXRαß and CS. A Kaplan-Meier Plotter database revealed reduced expression of LXRαß and ERß was correlated with low overall survival (OS). Thus, reduction of LXRαß expression by cigarette smoking may be one mechanism through which CS causes lung cancer. The possibility that maintenance of LXRαß and ERß signaling could be used in the treatment of NSCLC needs further investigation.