【原】《细胞》发表三阴性乳腺癌发生发展重要机制

　　2016年6月30日，美国《细胞》杂志发表哈佛医学院、达纳-法伯癌症研究所、布莱根妇女医院、斯克里普斯研究所、阿尔伯特·爱因斯坦医学院、北卡罗来纳大学、德克萨斯大学西南医学中心、霍华德·休斯医学研究所、芬兰奥卢大学细胞-基质研究中心的研究报告，证实三阴性乳腺癌旁分泌谷氨酸诱导缺氧诱导因子促进癌变。

　　乳腺癌表达雌激素受体、孕激素受体时，通常采用激素疗法来对其进行治疗，而对于表达HER2酪氨酸激酶的乳腺癌则常常是给予抗HER2治疗。三阴性乳腺癌是一类不表达上述受体且高度致命的癌症，当前迫切需要开发出针对三阴性乳腺癌的新疗法和生物标记物。

　　缺氧诱导因子是促进缺氧适应的转录因子，能够以环境依赖方式促进或抑制肿瘤生长。研究证实缺氧诱导因子在一些小鼠模型中促进了乳腺癌（包括三阴性乳腺癌）细胞的生长、侵袭与转移。

　　缺氧诱导因子由不稳定的α亚基和稳定的β亚基构成，缺氧诱导因子α在常氧条件下可被EglN的2-酮戊二酸依赖性双加氧酶脯氨酰羟化，EglN1是主要的缺氧诱导因子α脯氨酰羟化酶。pVHL泛素连接酶复合物可识别脯氨酰羟化缺氧诱导因子α，标记其进行蛋白酶体降解。

　　该研究证实三阴性乳腺癌细胞分泌谷氨酸，这是在常氧条件下这些细胞旁分泌诱导缺氧诱导因子1α的必要及充分条件。谷氨酸抑制了xCT谷氨酸-胱氨酸反向转运体摄取胱氨酸，导致了细胞内半胱氨酸耗竭。该研究通过生物化学分析及在细胞中证实，在缺乏半胱氨酸的条件下，EglN1经历氧化自我失活，由此抑制缺氧诱导因子α脯氨酰羟化酶。因此，EglN1能够感知氧气和半胱氨酸。

Cell. 2016 Jun 30;166(1):126-39.

Paracrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine.

Briggs KJ, Koivunen P, Cao S, Backus KM, Olenchock BA, Patel H, Zhang Q, Signoretti S, Gerfen GJ, Richardson AL, Witkiewicz AK, Cravatt BF, Clardy J, Kaelin WG Jr.

Dana-Farber Cancer Institute, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA; Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland; Harvard Medical School, Boston, MA, USA; The Scripps Research Institute, La Jolla, CA, USA; Albert Einstein College of Medicine, Bronx, NY, USA; University of North Carolina, Chapel Hill, NC, USA; University of Texas Southwestern Medical Center, Dallas, TX, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.

Highlights

• HIF1 promotes triple-negative breast carcinogenesis

• Triple-negative breast cancers secrete large amounts of glutamate

• Extracellular glutamate inhibits cystine uptake by the xCT antiporter

• Intracellular cysteine depletion directly inhibits the HIF prolyl-hydroxylases

The HIF transcription factor promotes adaptation to hypoxia and stimulates the growth of certain cancers, including triple-negative breast cancer (TNBC). The HIFα subunit is usually prolyl-hydroxylated by EglN family members under normoxic conditions, causing its rapid degradation. We confirmed that TNBC cells secrete glutamate, which we found is both necessary and sufficient for the paracrine induction of HIF1α in such cells under normoxic conditions. Glutamate inhibits the xCT glutamate-cystine antiporter, leading to intracellular cysteine depletion. EglN1, the main HIFα prolyl-hydroxylase, undergoes oxidative self-inactivation in the absence of cysteine both in biochemical assays and in cells, resulting in HIF1α accumulation. Therefore, EglN1 senses both oxygen and cysteine.

PMID: 27368101

PMCID: PMC4930557

DOI: 10.1016/j.cell.2016.05.042