Demas Diane M, Demo Susan, Fallah Yassi, Clarke Robert, Nephew Kenneth P, Althouse Sandra, Sandusky George, He Wei, Shajahan-Haq Ayesha N
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States.
Calithera Biosciences, South San Francisco, CA, United States.
Front Oncol. 2019 Aug 2;9:686. doi: 10.3389/fonc.2019.00686. eCollection 2019.
Dependence on the glutamine pathway is increased in advanced breast cancer cell models and tumors regardless of hormone receptor status or function. While 70% of breast cancers are estrogen receptor positive (ER+) and depend on estrogen signaling for growth, advanced ER+ breast cancers grow independent of estrogen. Cellular changes in amino acids such as glutamine are sensed by the mammalian target of rapamycin (mTOR) complex, mTORC1, which is often deregulated in ER+ advanced breast cancer. Inhibitor of mTOR, such as everolimus, has shown modest clinical activity in ER+ breast cancers when given with an antiestrogen. Here we show that breast cancer cell models that are estrogen independent and antiestrogen resistant are more dependent on glutamine for growth compared with their sensitive parental cell lines. Co-treatment of CB-839, an inhibitor of GLS, an enzyme that converts glutamine to glutamate, and everolimus interrupts the growth of these endocrine resistant xenografts. Using human tumor microarrays, we show that GLS is significantly higher in human breast cancer tumors with increased tumor grade, stage, ER-negative and progesterone receptor (PR) negative status. Moreover, GLS levels were significantly higher in breast tumors from African-American women compared with Caucasian women regardless of ER or PR status. Among patients treated with endocrine therapy, high GLS expression was associated with decreased disease free survival (DFS) from a multivariable model with GLS expression treated as dichotomous. Collectively, these findings suggest a complex biology for glutamine metabolism in driving breast cancer growth. Moreover, targeting GLS and mTOR in advanced breast cancer may be a novel therapeutic approach in advanced ER+ breast cancer.
在晚期乳腺癌细胞模型和肿瘤中，无论激素受体状态或功能如何，对谷氨酰胺途径的依赖性都会增加。虽然70%的乳腺癌是雌激素受体阳性（ER+），并且依赖雌激素信号来生长，但晚期ER+乳腺癌的生长不依赖雌激素。雷帕霉素哺乳动物靶点（mTOR）复合物mTORC1可感知谷氨酰胺等氨基酸的细胞变化，而mTORC1在ER+晚期乳腺癌中常常失调。mTOR抑制剂，如依维莫司，与抗雌激素联合使用时，在ER+乳腺癌中显示出适度的临床活性。我们在此表明，与敏感的亲本细胞系相比，雌激素非依赖性和抗雌激素耐药的乳腺癌细胞模型在生长方面更依赖谷氨酰胺。将GLS（一种将谷氨酰胺转化为谷氨酸的酶）的抑制剂CB-839与依维莫司联合使用，可阻断这些内分泌耐药异种移植物的生长。使用人类肿瘤微阵列，我们发现，在肿瘤分级、分期增加、ER阴性和孕激素受体（PR）阴性的人类乳腺癌肿瘤中，GLS显著更高。此外，无论ER或PR状态如何，非裔美国女性乳腺肿瘤中的GLS水平均显著高于白人女性。在内分泌治疗的患者中，从将GLS表达视为二分变量的多变量模型来看，高GLS表达与无病生存期（DFS）降低相关。总体而言，这些发现表明谷氨酰胺代谢在驱动乳腺癌生长方面具有复杂的生物学机制。此外，在晚期乳腺癌中靶向GLS和mTOR可能是晚期ER+乳腺癌的一种新的治疗方法。
