Lianto Priscilia, Hutchinson Samantha A, Moore J Bernadette, Hughes Thomas A, Thorne James L
School of Food Science and Nutrition, University of Leeds, Leeds LS2 9JT, UK.
The Institute of Cancer Research, Division of Cancer Therapeutics, London SM2 5NG, UK.
iScience. 2021 Oct 2;24(10):103212. doi: 10.1016/j.isci.2021.103212. eCollection 2021 Oct 22.
Activity of liver x receptor (LXR), the homeostatic regulator of cholesterol metabolism, is elevated in triple-negative breast cancer (BCa) relative to other BCa subtypes, driving drug resistance and metastatic gene signatures. The loci encoding LXRα and LXRβ produce multiple alternatively spliced proteins, but the true range of variants and their relevance to cancer remain poorly defined. Here, we report seven LXR splice variants, three of which have not previously been reported and five that were prognostic for disease-free survival. Expression of full-length LXRα splice variants was associated with poor prognosis, consistent with a role as an oncogenic driver of triple-negative tumor pathophysiology. Contrary to this was the observation that high expression of truncated LXRα splice variants or any LXRβ splice variant was associated with longer survival. These findings indicate that LXR isoform abundance is an important aspect of understanding the link between dysregulated cholesterol metabolism and cancer pathophysiology.
肝脏X受体（LXR）是胆固醇代谢的稳态调节因子，相对于其他乳腺癌（BCa）亚型，其三阴性乳腺癌中的活性升高，导致耐药性和转移基因特征。编码LXRα和LXRβ的基因座产生多种可变剪接蛋白，但变体的真实范围及其与癌症的相关性仍不清楚。在这里，我们报告了七种LXR剪接变体，其中三种以前未曾报道过，五种对无病生存期具有预后意义。全长LXRα剪接变体的表达与不良预后相关，这与作为三阴性肿瘤病理生理学致癌驱动因素的作用一致。与此相反的是，截短的LXRα剪接变体或任何LXRβ剪接变体的高表达与更长的生存期相关。这些发现表明，LXR异构体丰度是理解胆固醇代谢失调与癌症病理生理学之间联系的一个重要方面。
