Laboratory of Tumor Suppressor, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, South Korea.
Biochem Biophys Res Commun. 2012 Aug 24;425(2):436-42. doi: 10.1016/j.bbrc.2012.07.120. Epub 2012 Jul 28.
Breast cancer is the leading cause of deaths from cancer in women. Cancer recurrence is the most common cause of mortality in breast cancer patients. The cancer stem cell (CSC) hypothesis proposes that CSCs are the center of cancer development and recurrence. Targeting CSCs, in combination with standard chemotherapy, may prevent cancer recurrence and improve long-term survival. Stem cells can be enriched in non-adherent sphere cultures. To identify molecular targets in breast CSCs, we evaluated the transcription levels of stem cell-related genes in 4T1 mouse mammary cancer cells grown as spheres or in a monolayer culture. The most differentially expressed gene was found to be wingless-type MMTV integration site family member 1 (Wnt1) in the 4T1 sphere culture. Functionally, knockdown of Wnt1 in breast cancer cell lines suppressed the in vitro properties of the stem-like cells, including their sphere-forming ability and ALDH activity, whereas the addition of recombinant Wnt1 to breast cancer cell lines enhanced the in vitro properties of these stem-like cells. In addition, knockdown of Wnt1 in 4T1 cells affected the properties of the stem-like cells in vivo, including their tumorigenic potential and tumor initiation ability. Collectively, these results suggest that Wnt1 expression may give rise to the properties of CSCs in breast tumors. Therefore, targeting Wnt1-associated signaling proteins may provide an effective therapeutic approach for the treatment of advanced breast cancer.
乳腺癌是女性癌症死亡的主要原因。癌症复发是乳腺癌患者死亡的最常见原因。癌症干细胞（CSC）假说提出，CSC 是癌症发展和复发的核心。靶向 CSC 并结合标准化疗可能预防癌症复发并提高长期生存率。干细胞可在非贴壁球体培养中富集。为了鉴定乳腺癌 CSC 中的分子靶标，我们评估了在以球体或单层培养生长的 4T1 小鼠乳腺癌细胞中与干细胞相关的基因的转录水平。在 4T1 球体培养中，发现差异表达最明显的基因是 Wnt1。在乳腺癌细胞系中敲低 Wnt1 可抑制类干细胞的体外特性，包括其球体形成能力和 ALDH 活性，而向乳腺癌细胞系中添加重组 Wnt1 则增强了这些类干细胞的体外特性。此外，敲低 4T1 细胞中的 Wnt1 会影响体内类干细胞的特性，包括其致瘤潜能和肿瘤起始能力。总之，这些结果表明 Wnt1 表达可能赋予乳腺癌肿瘤中 CSC 的特性。因此，靶向 Wnt1 相关信号蛋白可能为治疗晚期乳腺癌提供有效的治疗方法。
