Liver x receptor alpha drives chemoresistance in response to side-chain hydroxycholesterols in triple negative breast cancer.
Liver x receptor alpha drives chemoresistance in response to side-chain hydroxycholesterols in triple negative breast cancer.
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DOI：
10.1038/s41388-021-01720-w
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发表时间：
2021-04
期刊：
影响因子：
8
通讯作者：
Thorne JL
中科院分区：
文献类型：
--
作者：
Hutchinson SA;Websdale A;Cioccoloni G;Røberg-Larsen H;Lianto P;Kim B;Rose A;Soteriou C;Pramanik A;Wastall LM;Williams BJ;Henn MA;Chen JJ;Ma L;Moore JB;Nelson E;Hughes TA;Thorne JL
三阴性乳腺癌（TNBC）是具有挑战性的成功治疗，因为靶向治疗不存在。相反，全身治疗通常限于细胞毒性化疗，这在循环胆固醇升高的患者中更常见。肝脏x受体是配体依赖性转录因子，是胆固醇的稳态调节因子，与非肿瘤组织中广泛亲和性外源性转运蛋白活性的调节有关。我们表明，LXR配体赋予TNBC细胞系和异种移植物的化疗耐药性，LXR α是必要的，足以介导这种耐药性。此外，在肿瘤复发的TNBC患者中，LXR α和配体是预后不良的独立标志物，并与P-糖蛋白表达相关。然而，在疾病幸存的患者中，LXR α信号传导和P-糖蛋白是解耦的。这些数据揭示了这种预后不良的乳腺癌亚型的一种新的化疗耐药机制。我们的结论是，在一些TNBC患者的全身化疗失败是由共同选择LXR α：P-糖蛋白轴，已用于预防和治疗其他疾病的治疗高度靶向的途径。
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.
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影响因子：
5.3
作者：
CLARE, K;HARDWICK, SJ;MITCHINSON, MJ
通讯作者：
MITCHINSON, MJ
DOI：
10.1016/j.jsbmb.2019.105390
发表时间：
2019-09-01
影响因子：
4.1
作者：
Bauriaud-Mallet, Mathilde;Vija-Racaru, Lavinia;Silvente-Poirot, Sandrine
通讯作者：
Silvente-Poirot, Sandrine
影响因子：
4.8
作者：
Shahoei, Sayyed Hamed;Kim, Young-Chae;Nelson, Erik R.
通讯作者：
Nelson, Erik R.
影响因子：
45.3
作者：
Liedtke, Cornelia;Mazouni, Chafika;Pusztai, Lajos
通讯作者：
Pusztai, Lajos
DOI：
10.1186/bcr3493
发表时间：
2013-10-01
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Eccles SA;Aboagye EO;Ali S;Anderson AS;Armes J;Berditchevski F;Blaydes JP;Brennan K;Brown NJ;Bryant HE;Bundred NJ;Burchell JM;Campbell AM;Carroll JS;Clarke RB;Coles CE;Cook GJ;Cox A;Curtin NJ;Dekker LV;Silva Idos S;Duffy SW;Easton DF;Eccles DM;Edwards DR;Edwards J;Evans D;Fenlon DF;Flanagan JM;Foster C;Gallagher WM;Garcia-Closas M;Gee JM;Gescher AJ;Goh V;Groves AM;Harvey AJ;Harvie M;Hennessy BT;Hiscox S;Holen I;Howell SJ;Howell A;Hubbard G;Hulbert-Williams N;Hunter MS;Jasani B;Jones LJ;Key TJ;Kirwan CC;Kong A;Kunkler IH;Langdon SP;Leach MO;Mann DJ;Marshall JF;Martin L;Martin SG;Macdougall JE;Miles DW;Miller WR;Morris JR;Moss SM;Mullan P;Natrajan R;O'Connor JP;O'Connor R;Palmieri C;Pharoah PD;Rakha EA;Reed E;Robinson SP;Sahai E;Saxton JM;Schmid P;Smalley MJ;Speirs V;Stein R;Stingl J;Streuli CH;Tutt AN;Velikova G;Walker RA;Watson CJ;Williams KJ;Young LS;Thompson AM
通讯作者：
Thompson AM