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

Abstract

Liver X receptors (LXRαβ) 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 LXRαβ -/- mice develop squamous cell lung cancer. We now report that those LXRαβ -/- 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 TGFβ signaling; an increased expression of matrix metalloproteinases accompanied by degradation of lung collagen; and a loss of estrogen receptor β (ERβ). Because NSCLC is associated with cigarette smoking, we investigated the possible links between loss of LXRαβ and CS. A Kaplan-Meier Plotter database revealed reduced expression of LXRαβ and ERβ was correlated with low overall survival (OS). Thus, reduction of LXRαβ expression by cigarette smoking may be one mechanism through which CS causes lung cancer. The possibility that maintenance of LXRαβ and ERβ signaling could be used in the treatment of NSCLC needs further investigation.

Loss of ERβ in Aging LXRαβ Knockout Mice Leads to Colitis

“…One possible explanation for the changes in the colonic mucosa as mice age is the rapid turnover of the surface epithelium with an overall consequence on a less-welldifferentiated surface epithelium. Late-onset phenotype characteristics of LXR −/− mice have been reported in dopaminergic neurons in the substantia nigra [41], large motor neurons in the ventral horn of the spinal cord [42], retinal ganglion cells in the eye [21], spiral ganglion neurons in the cochlea [22], and squamous cell lung cancer, a rare subtype of non-small cell lung cancer, in LXRαβ −/− mice [16,43]. In the case of non-small cell lung cancer, there was a loss of ERβ expression which contributed to increased proliferation.…”

“…The aim of this study was to investigate the mechanisms through which loss of LXRs leads to the sensitivity of the colon to colitis. We were particularly interested in the possibility that ERβ signaling was involved because of the colonic phenotype of ERβ mice and our finding of the loss of ERβ in the lungs of LXRαβ −/− mice: aging LXRαβ −/− lungs developed a rare form of lung cancer after mice turned 13 months of age [16]. The hypothesis that we are testing is that loss of ERβ is a key factor in the development of the phenotype in LXRαβ −/− mice because of the loss of the antiproliferative role of ERβ in epithelial cells.…”