Hutchinson Samantha A, Websdale Alex, Cioccoloni Giorgia, Røberg-Larsen Hanne, Lianto Priscilia, Kim Baek, Rose Ailsa, Soteriou Chrysa, Pramanik Arindam, Wastall Laura M, Williams Bethany J, Henn Madeline A, Chen Joy J, Ma Liqian, Moore J Bernadette, Nelson Erik, Hughes Thomas A, Thorne James L
School of Food Science and Nutrition, University of Leeds, Leeds, UK.
Institute for Cancer Research, London, UK.
Oncogene. 2021 Apr;40(16):2872-2883. doi: 10.1038/s41388-021-01720-w. Epub 2021 Mar 19.
Triple negative breast cancer (TNBC) is challenging to treat successfully because targeted therapies do not exist. Instead, systemic therapy is typically restricted to cytotoxic chemotherapy, which fails more often in patients with elevated circulating cholesterol. Liver x receptors are ligand-dependent transcription factors that are homeostatic regulators of cholesterol, and are linked to regulation of broad-affinity xenobiotic transporter activity in non-tumor tissues. We show that LXR ligands confer chemotherapy resistance in TNBC cell lines and xenografts, and that LXRalpha is necessary and sufficient to mediate this resistance. Furthermore, in TNBC patients who had cancer recurrences, LXRalpha and ligands were independent markers of poor prognosis and correlated with P-glycoprotein expression. However, in patients who survived their disease, LXRalpha signaling and P-glycoprotein were decoupled. These data reveal a novel chemotherapy resistance mechanism in this poor prognosis subtype of breast cancer. We conclude that systemic chemotherapy failure in some TNBC patients is caused by co-opting the LXRalpha:P-glycoprotein axis, a pathway highly targetable by therapies that are already used for prevention and treatment of other diseases.
三阴性乳腺癌（TNBC）因不存在靶向治疗方法，所以成功治疗颇具挑战性。相反，全身治疗通常局限于细胞毒性化疗，而这种化疗在循环胆固醇升高的患者中更常失败。肝脏X受体是依赖配体的转录因子，是胆固醇的稳态调节因子，并与非肿瘤组织中广泛亲和力的外源性物质转运体活性调节有关。我们发现，肝脏X受体配体在TNBC细胞系和异种移植模型中赋予化疗抗性，并且肝脏X受体α（LXRα）对于介导这种抗性是必要且充分的。此外，在癌症复发的TNBC患者中，LXRα和配体是预后不良的独立标志物，且与P-糖蛋白表达相关。然而，在疾病存活的患者中，LXRα信号传导和P-糖蛋白解偶联。这些数据揭示了这种预后不良的乳腺癌亚型中的一种新的化疗抗性机制。我们得出结论，一些TNBC患者的全身化疗失败是由LXRα：P-糖蛋白轴的协同作用引起的，这是一条可被已用于预防和治疗其他疾病的疗法高度靶向的途径。
