Breast cancer stem cells (CSCs) are distinct CD44⁺-subpopulations that are involved in metastasis and chemoresistance. However, the underlying molecular mechanism of CD44 in breast CSCs-mediated tumorigenesis remains elusive. We observed high CD44 expression in advanced-stage clinical breast tumor samples. CD44 activation in breast CSCs sorted from various triple negative breast cancer (TNBC) cell lines induced proliferation, migration, invasion, mammosphere formation that were reversed in presence of inhibitor, 4-methyl umbelliferone or CD44 silencing. CD44 activation in breast CSCs induced Src, Akt, and nuclear translocation of pSTAT3. PCR arrays revealed differential expression of a metabolic gene, Lipoprotein lipase (LPL), and transcription factor, SNAI3. Differential transcriptional regulation of LPL by pSTAT3 and SNAI3 was confirmed by promoter-reporter and chromatin immunoprecipitation analysis. Orthotopic xenograft murine breast tumor model revealed high tumorigenicity of CD24⁻/CD44⁺-breast CSCs as compared with CD24⁺-breast cancer cells. Furthermore, stable breast CSCs-CD44 shRNA and/or intratumoral administration of Tetrahydrolipstatin (LPL inhibitor) abrogated tumor progression and neoangiogenesis. Thus, LPL serves as a potential target for an efficacious therapeutics against aggressive breast cancer.

乳腺癌干细胞 (CSC) 是独特的 CD44 ^{+ -}亚群，涉及转移和化学抗性。然而，CD44 在乳腺 CSCs 介导的肿瘤发生中的潜在分子机制仍然难以捉摸。我们在晚期临床乳腺肿瘤样本中观察到高 CD44 表达。来自各种三阴性乳腺癌 (TNBC) 细胞系的乳腺 CSC 中的 CD44 激活诱导增殖、迁移、侵袭、乳腺球形成，这些在抑制剂、4-甲基伞形酮或 CD44 沉默的存在下被逆转。乳腺 CSC 中的 CD44 激活诱导 Src、Akt 和 pSTAT3 的核易位。PCR 阵列揭示了代谢基因脂蛋白脂肪酶 ( LPL ) 和转录因子SNAI3 的差异表达. 通过启动子-报告基因和染色质免疫沉淀分析证实了 pSTAT3 和 SNAI3对LPL的差异转录调控。原位异种移植鼠乳腺肿瘤模型显示，与 CD24 ⁺ -乳腺癌细胞相比，CD24 ^- /CD44 ^{+ -}乳腺癌 CSC 具有高致瘤性。此外，稳定的乳腺 CSCs-CD44 shRNA 和/或Tetrahydrolipstatin（LPL 抑制剂）的瘤内给药阻止了肿瘤进展和新血管生成。因此，LPL可作为有效治疗侵袭性乳腺癌的潜在靶点。