ELF5 Drives Lung Metastasis in Luminal Breast Cancer through Recruitment of Gr1+ CD11b+ Myeloid-Derived Suppressor Cells.
ELF5 Drives Lung Metastasis in Luminal Breast Cancer through Recruitment of Gr1+ CD11b+ Myeloid-Derived Suppressor Cells.
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DOI：
10.1371/journal.pbio.1002330
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发表时间：
2015-12
期刊：
影响因子：
9.8
通讯作者：
Ormandy CJ
中科院分区：
文献类型：
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作者：
Gallego-Ortega D;Ledger A;Roden DL;Law AM;Magenau A;Kikhtyak Z;Cho C;Allerdice SL;Lee HJ;Valdes-Mora F;Herrmann D;Salomon R;Young AI;Lee BY;Sergio CM;Kaplan W;Piggin C;Conway JR;Rabinovich B;Millar EK;Oakes SR;Chtanova T;Swarbrick A;Naylor MJ;O'Toole S;Green AR;Timpson P;Gee JM;Ellis IO;Clark SJ;Ormandy CJ
在妊娠期间，ETS转录因子ELF 5通过驱动乳腺腔祖细胞的细胞命运决定来建立分泌乳汁的肺泡细胞谱系。在乳腺癌中，ELF 5是肿瘤亚型的关键转录决定因子，并与抗雌激素治疗不敏感性的发展有关。在腔型乳腺癌的小鼠乳腺肿瘤病毒-多瘤中T（MMTV-PyMT）模型中，ELF 5水平的诱导增加了原发性肿瘤中的白细胞浸润、血管生成和血管渗透性，并且大大增加了肺转移的大小和数量。髓源性抑制细胞，一组未成熟的中性粒细胞最近被确定为血管发生和转移的介质，被招募到肿瘤ELF 5。使用特异性Ly 6 G抗体耗尽这些细胞阻止ELF 5驱动血管发生和转移。管腔A型乳腺癌中的表达特征表明，髓样细胞浸润和炎症增加与ELF 5表达相关，ELF 5免疫组化染色增加预测管腔A型患者的无转移和总生存期要短得多，定义了一组意外经历早期疾病进展的患者。因此，在MMTV-PyMT小鼠乳腺模型中，增加的ELF 5水平通过吸收先天免疫系统来驱动转移。由于ELF 5以前已经被牵连在抗雌激素耐药性的发展，这一发现牵连ELF 5作为一个决定性因素，在获得的关键方面的致命表型在管腔A乳腺癌。肿瘤中转录因子ELF 5的上调有助于创造一个微环境，该微环境招募先天免疫系统并增加血管通透性，导致管腔乳腺癌转移增加。连同其在抗雌激素抗性中的作用，这表明ELF 5是致死表型的主要驱动因素。转录因子Elf 5定义了对乳腺癌不敏感和内分泌治疗耐药的乳腺癌。在这项研究中，我们发现ELF 5驱动肿瘤细胞扩散到肺部。我们证明了这种转移性扩散的潜在机制是通过先天免疫系统的募集。有趣的是，这种作用能够克服ELF 5对癌细胞的其他肿瘤抑制作用，例如增殖，运动和侵袭减少。这一重要发现挑战了更传统的观点，即转移活性的最有效决定因素位于癌细胞内。我们清楚地表明，先天免疫系统强烈影响癌细胞的转移活性，尽管它们具有细胞内在的扩散潜力。我们以前的工作表明，在管腔型乳腺癌中，ELF 5是抗雌激素治疗抵抗的关键决定因素。在这里，我们表明，由ELF 5驱动的转移机制在管腔型乳腺癌患者中是最重要的，在这些患者中，较高的ELF 5表达与细胞毒性T淋巴细胞（一种负责肿瘤排斥反应的免疫细胞群）的低存在相关。因此，我们现在看到ELF 5可能是导致管腔型乳腺癌向致死表型发展的两个最重要过程的背后;对抗雌激素治疗的抗性和转移活性的发展。这种理解可以为设计新的治疗策略和开发新的预测测试铺平道路。
During pregnancy, the ETS transcription factor ELF5 establishes the milk-secreting alveolar cell lineage by driving a cell fate decision of the mammary luminal progenitor cell. In breast cancer, ELF5 is a key transcriptional determinant of tumor subtype and has been implicated in the development of insensitivity to anti-estrogen therapy. In the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT) model of luminal breast cancer, induction of ELF5 levels increased leukocyte infiltration, angiogenesis, and blood vessel permeability in primary tumors and greatly increased the size and number of lung metastasis. Myeloid-derived suppressor cells, a group of immature neutrophils recently identified as mediators of vasculogenesis and metastasis, were recruited to the tumor in response to ELF5. Depletion of these cells using specific Ly6G antibodies prevented ELF5 from driving vasculogenesis and metastasis. Expression signatures in luminal A breast cancers indicated that increased myeloid cell invasion and inflammation were correlated with ELF5 expression, and increased ELF5 immunohistochemical staining predicted much shorter metastasis–free and overall survival of luminal A patients, defining a group who experienced unexpectedly early disease progression. Thus, in the MMTV-PyMT mouse mammary model, increased ELF5 levels drive metastasis by co-opting the innate immune system. As ELF5 has been previously implicated in the development of antiestrogen resistance, this finding implicates ELF5 as a defining factor in the acquisition of the key aspects of the lethal phenotype in luminal A breast cancer. Up-regulation of the transcription factor ELF5 in tumors helps to create a micro-environment that recruits the innate immune system and increases vascular permeability, leading to increased metastasis in luminal breast cancer. Together with its role in anti-estrogen resistance, this suggests that ELF5 is a major driver of a lethal phenotype. The transcription factor Elf5 defines hormone-insensitive and endocrine-therapy–resistant breast cancer. In this study, we have discovered that ELF5 drives the spread of tumor cells to the lungs. We demonstrate that the underlying mechanism for this metastatic spread is via recruitment of the innate immune system. Interestingly, this effect is able to overcome the other tumor-suppressive effects of ELF5 on cancer cells, such as reduced proliferation, motility, and invasion. This important finding challenges the more conventional view that the most potent determinant of metastatic activity lies within the cancer cell. We clearly demonstrate that the innate immune system strongly influences the metastatic activity of cancer cells despite their cell-intrinsic spread potential. Our previous work demonstrated that in luminal breast cancer, ELF5 is a key determinant of antiestrogen therapy resistance. Here, we show that the metastatic mechanism driven by ELF5 is most important in luminal breast cancer patients, in whom higher ELF5 expression is associated with low presence of cytotoxic T lymphocytes, an immune cell population responsible for tumor rejection. Thus, we now see that ELF5 may be behind the two most important processes that cause luminal breast cancers to progress towards the lethal phenotype; resistance to antiestrogen therapy and the development of metastatic activity. This understanding could pave the way for new therapeutic strategies to be devised and new predictive tests to be developed.