The development of efficacious therapies targeting metastatic spread of breast cancer to the brain represents an unmet clinical need. Accordingly, an improved understanding of the molecular underpinnings of central nervous system spread and progression of breast cancer brain metastases (BCBM) is required. In this study, the clinical burden of disease in BCBM was investigated, as well as the role of aldehyde dehydrogenase 1A3 (ALDH1A3) in the metastatic cascade leading to BCBM development. Initial analysis of clinical survival trends for breast cancer and BCBM determined improvement of breast cancer survival rates; however, this has failed to positively affect the prognostic milestones of triple-negative breast cancer (TNBC) brain metastases (BM). ALDH1A3 and a representative epithelial–mesenchymal transition (EMT) gene signature (mesenchymal markers, CD44 or Vimentin) were compared in tumors derived from BM, lung metastases (LM), or bone metastases (BoM) of patients as well as mice after injection of TNBC cells. Selective elevation of the EMT signature and ALDH1A3 were observed in BM, unlike LM and BoM, especially in the tumor edge. Furthermore, ALDH1A3 was determined to play a role in BCBM establishment via regulation of circulating tumor cell adhesion and migration phases in the BCBM cascade. Validation through genetic and pharmacologic inhibition of ALDH1A3 via lentiviral shRNA knockdown and a novel small-molecule inhibitor demonstrated selective inhibition of BCBM formation with prolonged survival of tumor-bearing mice. Given the survival benefits via targeting ALDH1A3, it may prove an effective therapeutic strategy for BCBM prevention and/or treatment.

中文翻译：

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鉴定 ALDH1A3 作为乳腺癌转移起始细胞的可行治疗靶点

针对乳腺癌转移性扩散到大脑的有效疗法的开发代表了未满足的临床需求。因此，需要更好地了解乳腺癌脑转移（BCBM）的中枢神经系统扩散和进展的分子基础。在这项研究中，研究了 BCBM 的临床疾病负担，以及乙醛脱氢酶 1A3 (ALDH1A3) 在导致 BCBM 发展的转移级联中的作用。对乳腺癌临床生存趋势和 BCBM 的初步分析确定了乳腺癌生存率的提高；然而，这未能对三阴性乳腺癌（TNBC）脑转移（BM）的预后里程碑产生积极影响。在注射 ALDH1A3 后，在患者和小鼠的 BM、肺转移 (LM) 或骨转移 (BoM) 衍生的肿瘤中比较 ALDH1A3 和代表性上皮间质转化 (EMT) 基因特征（间质标记物、CD44 或波形蛋白） TNBC 细胞。与 LM 和 BoM 不同，在 BM 中观察到 EMT 特征和 ALDH1A3 选择性升高，尤其是在肿瘤边缘。此外，ALDH1A3 被确定通过调节 BCBM 级联中的循环肿瘤细胞粘附和迁移阶段在 BCBM 建立中发挥作用。通过慢病毒 shRNA 敲低和新型小分子抑制剂对 ALDH1A3 的遗传和药理学抑制进行验证，证明可以选择性抑制 BCBM 形成，延长荷瘤小鼠的存活时间。鉴于通过靶向 ALDH1A3 带来的生存益处，它可能被证明是 BCBM 预防和/或治疗的有效治疗策略。