Combined Targeting of Estrogen Receptor Alpha and Exportin 1 in Metastatic Breast Cancers.
Combined Targeting of Estrogen Receptor Alpha and Exportin 1 in Metastatic Breast Cancers.
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DOI：
10.3390/cancers12092397
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发表时间：
2020-08-24
期刊：
影响因子：
5.2
通讯作者：
Madak-Erdogan Z
中科院分区：
文献类型：
--
作者：
Cotul EK;Zuo Q;Santaliz-Casiano A;Imir OB;Mogol AN;Tunc E;Duong K;Lee JK;Ramesh R;Odukoya E;Kesavadas MP;Ziogaite M;Smith BP;Mao C;Shapiro DJ;Park BH;Katzenellenbogen BS;Daly D;Aranda E;O'Neill JD;Walker C;Landesman Y;Madak-Erdogan Z
在雌激素受体阳性（ER+）肿瘤的女性中，大多数乳腺癌特异性死亡是由于肿瘤转移对治疗产生耐药性。在转移性ER+肿瘤中，迫切需要新的治疗方法来实现肿瘤消退和/或维持治疗反应性。本研究的目的是阐明代谢途径在雌激素受体阳性乳腺癌中破坏治疗效果的作用。我们之前的研究发现，核输出蛋白exintin 1 （XPO1）在内分泌耐药性进展中起重要作用，并表明联合selinexor (SEL) （fda批准的XPO1拮抗剂）与内分泌药物协同作用并提供持续的肿瘤消退。在当前的研究中，我们结合转录组学、代谢组学和代谢通量实验，确定了内分泌抵抗过程中某些线粒体通路的上调。当内分泌抵抗细胞在模拟营养剥夺肿瘤微环境的培养基条件下用单一药物处理时，它们对线粒体呼吸持续的谷氨酰胺依赖性增加。谷氨酰胺的作用取决于谷氨酰胺转化为谷氨酸和NAD+的生成。PGC1α是代谢的关键调节因子，是重新连接代谢表型的主要驱动因素。在内分泌抵抗性乳腺肿瘤中，重塑代谢途径以再生新的脆弱性是一种新方法，我们的研究结果揭示了ERα-XPO1串扰在减少癌症复发中发挥的关键作用。将SEL与目前用于ER+转移性乳腺癌临床管理的治疗方法相结合，有望在已经转移的患者中治疗并保持这些癌症对治疗的反应。
The majority of breast cancer specific deaths in women with estrogen receptor positive (ER+) tumors occur due to metastases that are resistant to therapy. There is a critical need for novel therapeutic approaches to achieve tumor regression and/or maintain therapy responsiveness in metastatic ER+ tumors. The objective of this study was to elucidate the role of metabolic pathways that undermine therapy efficacy in ER+ breast cancers. Our previous studies identified Exportin 1 (XPO1), a nuclear export protein, as an important player in endocrine resistance progression and showed that combining selinexor (SEL), an FDA-approved XPO1 antagonist, synergized with endocrine agents and provided sustained tumor regression. In the current study, using a combination of transcriptomics, metabolomics and metabolic flux experiments, we identified certain mitochondrial pathways to be upregulated during endocrine resistance. When endocrine resistant cells were treated with single agents in media conditions that mimic a nutrient deprived tumor microenvironment, their glutamine dependence for continuation of mitochondrial respiration increased. The effect of glutamine was dependent on conversion of the glutamine to glutamate, and generation of NAD+. PGC1α, a key regulator of metabolism, was the main driver of the rewired metabolic phenotype. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and our findings reveal a critical role that ERα-XPO1 crosstalk plays in reducing cancer recurrences. Combining SEL with current therapies used in clinical management of ER+ metastatic breast cancer shows promise for treating and keeping these cancers responsive to therapies in already metastasized patients.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
影响因子：
3.8
作者：
Bean JR;Hosford SR;Symonds LK;Owens P;Dillon LM;Yang W;Shee K;Schwartz GN;Marotti JD;Muller KE;Rosenkranz KM;Barth RJ;Chen VS;Agarwal VR;Miller TW
通讯作者：
Miller TW
影响因子：
45.3
作者：
Jatoi, Ismail;Chen, Bingshu E.;Rosenberg, Philip S.
通讯作者：
Rosenberg, Philip S.
影响因子：
28.1
作者：
Carpenter, Ryan A.;Kwak, Jun-Goo;Lee, Jungwoo
通讯作者：
Lee, Jungwoo