Bindeman Wendy E, Corn Kevin C, Rafat Marjan, Fingleton Barbara
Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA.
Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA.
Clin Exp Metastasis. 2025 Jul 15;42(5):40. doi: 10.1007/s10585-025-10362-1.
Triple-negative breast cancer is associated with poor patient prognosis and high rates of distant metastasis. These patients are at elevated risk of brain metastasis, which remains a major therapeutic challenge. IL13RA2, a high-affinity receptor for IL13, is highly expressed in primary brain cancers, many extracranial solid tumors, and in lung- and brain-seeking metastatic variant cell lines. However, the relationship between IL13RA2 and patient prognosis is variable, and the biological function of this receptor in cancer remains controversial. We sought to define the role of IL13RA2 in triple-negative breast cancer growth and metastasis, with an emphasis on breast-to-brain metastasis. We generated IL13RA2-CRISPR knockout derivatives of the human brain-seeking breast cancer cell line MDA231BrM2, as well as murine 4T1 cells, and evaluated changes in gene expression, proliferation, survival, and metastatic growth in vivo. Both IL13RA2-deficient models demonstrate enhanced cell survival in vitro, as well as augmented metastatic tumor growth and worsened animal survival in intracardiac models of brain metastasis. Concordantly, elevated IL13RA2 mRNA expression is positively correlated with overall survival in patients with basal-like breast cancer. Mechanistically, IL13RA2-deficient cells exhibit increased AKT and NF-κB signaling. These cells are sensitive to inhibition of either pathway, but especially AKT, which may represent a clinically useful vulnerability for patients with IL13RA2-low tumors. Our data suggest that inhibition of IL13RA2, though promising in other tumor contexts, may be deleterious in metastatic triple-negative breast cancer.
三阴性乳腺癌与患者预后不良及远处转移率高相关。这些患者发生脑转移的风险升高，而脑转移仍然是一个重大的治疗挑战。IL13RA2是IL13的高亲和力受体，在原发性脑癌、许多颅外实体瘤以及趋向肺和脑的转移变异细胞系中高度表达。然而，IL13RA2与患者预后的关系并不一致，该受体在癌症中的生物学功能仍存在争议。我们试图确定IL13RA2在三阴性乳腺癌生长和转移中的作用，重点是乳腺癌向脑转移。我们构建了趋向脑的人乳腺癌细胞系MDA231BrM2以及小鼠4T1细胞的IL13RA2 - CRISPR基因敲除衍生物，并评估了体内基因表达、增殖、存活和转移生长的变化。两种IL13RA2缺陷模型均显示体外细胞存活增强，以及在脑转移的心内模型中转移瘤生长增加和动物存活恶化。与此一致，在基底样乳腺癌患者中，IL13RA2 mRNA表达升高与总生存期呈正相关。从机制上讲，IL13RA2缺陷细胞表现出AKT和NF-κB信号增强。这些细胞对任何一条通路的抑制都敏感，但对AKT尤其敏感，这可能代表IL13RA2低表达肿瘤患者临床上有用的脆弱点。我们的数据表明，抑制IL13RA2虽然在其他肿瘤背景下有前景，但在转移性三阴性乳腺癌中可能是有害的。
