The discovery of genes and molecular pathways involved in the formation of brain metastasis would direct the development of therapeutic strategies to prevent this deadly complication of cancer. By comparing gene expression profiles of Estrogen Receptor negative (ER-) primary breast tumors between patients who developed metastasis to brain and to organs other than brain, we found that T lymphocytes promote the formation of brain metastases. To functionally test the ability of T cells to promote brain metastasis, we used an in vitro blood–brain barrier (BBB) model. By co-culturing T lymphocytes with breast cancer cells, we confirmed that T cells increase the ability of breast cancer cells to cross the BBB. Proteomics analysis of the tumor cells revealed Guanylate-Binding Protein 1 (GBP1) as a key T lymphocyte-induced protein that enables breast cancer cells to cross the BBB. The GBP1 gene appeared to be up-regulated in breast cancer of patients who developed brain metastasis. Silencing of GBP1 reduced the ability of breast cancer cells to cross the in vitro BBB model. In addition, the findings were confirmed in vivo in an immunocompetent syngeneic mouse model. Co-culturing of ErbB2 tumor cells with activated T cells induced a significant increase in Gbp1 expression by the cancer cells. Intracardial inoculation of the co-cultured tumor cells resulted in preferential seeding to brain. Moreover, intracerebral outgrowth of the tumor cells was demonstrated. The findings point to a role of T cells in the formation of brain metastases in ER- breast cancers, and provide potential targets for intervention to prevent the development of cerebral metastases.

涉及脑转移形成的基因和分子途径的发现将指导治疗策略的发展，以预防这种致命的癌症并发症。通过比较发生转移至大脑和除大脑以外器官的患者之间的雌激素受体阴性（ER-）原发性乳腺肿瘤的基因表达谱，我们发现T淋巴细胞促进了脑转移的形成。为了功能上测试T细胞促进脑转移的能力，我们使用了体外血脑屏障（BBB）模型。通过将T淋巴细胞与乳腺癌细胞共同培养，我们证实T细胞增加了乳腺癌细胞穿越BBB的能力。对肿瘤细胞的蛋白质组学分析显示，鸟苷酸结合蛋白1（GBP1）是T细胞诱导的关键蛋白，可使乳腺癌细胞穿过BBB。这在发生脑转移的患者的乳腺癌中，GBP1基因似乎被上调。GBP1的沉默降低了乳腺癌细胞穿越体外BBB模型的能力。另外，该发现在具有免疫能力的同系小鼠模型中在体内得到证实。ErbB2肿瘤细胞与活化T细胞的共培养可诱导癌细胞的Gbp1表达显着增加。共培养的肿瘤细胞的心内接种导致向脑的优先播种。此外，证实了肿瘤细胞的脑内生长。这些发现指出，T细胞在ER-乳腺癌中脑转移瘤的形成中发挥了作用，并为预防脑转移瘤的发展提供了潜在的靶标。