Comprehensive profiling of liver x receptor splicing in triple negative breast cancer reveals existence of novel splice variants that are prognostic for survival

Abstract

The liver x receptors (LXR) alpha and beta are ligand-responsive transcription factors that link homeostatic control of lipid metabolism with cancer pathophysiology and prognosis. LXR activity is elevated in triple negative breast cancer relative to other breast cancer subtypes, driving gene signatures associated with drug resistance and metastasis. The loci encoding LXR and LXR{beta} produce multiple alternatively spliced proteins, but the true range of variants and their relevance to cancer remain poorly defined. Seven splice variants of LXR or LXR{beta} were detected. Three have not been recorded previously and five were prognostic. High expression of full length LXR was associated with shorter disease-free survival but splice variants harbouring truncations of the ligand binding domain were prognostic for improved survival. All LXR{beta} variants were associated with longer disease-free survival. Mechanistically, while full length LXR positively correlated with target gene expression in primary samples, LXR{beta} was inversely correlated. We conclude that canonical LXR function is an oncogenic driver of triple negative tumour pathophysiology that can be countered by high expression of truncated splice variants and/or full length LXR{beta}. HighlightsO_LIExpression of full length LXR is associated with shorter disease-free survival of triple negative breast cancer patients C_LIO_LIA systematic evaluation of cell lines and primary tumour samples indicates LXR splicing is extensive in breast cancer C_LIO_LIConfirmation of three new LXR splice variants at transcript and protein level C_LIO_LIExpression of full length LXR{beta} or LXR splice variants that harbour truncated ligand binding domains are associated with better prognosis C_LIO_LIExpression of LXR target genes is positively correlated with LXR in relapsed patients and inversely correlated with LXR{beta} in survivors. C_LI