Chiche A, Moumen M, Romagnoli M, Petit V, Lasla H, Jézéquel P, de la Grange P, Jonkers J, Deugnier M-A, Glukhova M A, Faraldo M M
Institut Curie, PSL Research University, CNRS, UMR144, Paris, France.
Institut de Cancérologie de l'Ouest, Bvd Jacques Monod, Saint Herblain, France.
Oncogene. 2017 Apr 27;36(17):2355-2365. doi: 10.1038/onc.2016.396. Epub 2016 Oct 24.
Triple-negative breast cancer is a heterogeneous disease characterized by the expression of basal cell markers, no estrogen or progesterone receptor expression and a lack of HER2 overexpression. Triple-negative tumors often display activated Wnt/β-catenin signaling and most have impaired p53 function. We studied the interplay between p53 loss and Wnt/β-catenin signaling in stem cell function and tumorigenesis, by deleting p53 from the mammary epithelium of K5ΔNβcat mice displaying a constitutive activation of Wnt/β-catenin signaling in basal cells. K5ΔNβcat transgenic mice present amplification of the basal stem cell pool and develop triple-negative mammary carcinomas. The loss of p53 in K5ΔNβcat mice led to an early expansion of mammary stem/progenitor cells and accelerated the formation of triple-negative tumors. In particular, p53-deficient tumors expressed high levels of integrins and extracellular matrix components and were enriched in cancer stem cells. They also overexpressed the tyrosine kinase receptor Met, a feature characteristic of human triple-negative breast tumors. The inhibition of Met kinase activity impaired tumorsphere formation, demonstrating the requirement of Met signaling for cancer stem cell growth in this model. Human basal-like breast cancers with predicted mutated p53 status had higher levels of MET expression than tumors with wild-type p53. These results connect p53 loss and β-catenin activation to stem cell regulation and tumorigenesis in triple-negative cancer and highlight the role of Met signaling in maintaining cancer stem cell properties, revealing new cues for targeted therapies.
三阴性乳腺癌是一种异质性疾病，其特征为基底细胞标志物表达、无雌激素或孕激素受体表达以及缺乏HER2过表达。三阴性肿瘤通常表现出Wnt/β-连环蛋白信号激活，且大多数具有p53功能受损。我们通过从K5ΔNβcat小鼠的乳腺上皮中删除p53，研究了p53缺失与Wnt/β-连环蛋白信号在干细胞功能和肿瘤发生中的相互作用，K5ΔNβcat小鼠的基底细胞中Wnt/β-连环蛋白信号呈组成性激活。K5ΔNβcat转基因小鼠的基底干细胞池扩增，并发生三阴性乳腺癌。K5ΔNβcat小鼠中p53的缺失导致乳腺干/祖细胞早期扩增，并加速三阴性肿瘤的形成。特别是，p53缺陷型肿瘤表达高水平的整合素和细胞外基质成分，且富含癌症干细胞。它们还过表达酪氨酸激酶受体Met，这是人类三阴性乳腺肿瘤的一个特征。抑制Met激酶活性会损害肿瘤球形成，证明在该模型中癌症干细胞生长需要Met信号。预测p53状态突变的人类基底样乳腺癌比野生型p53肿瘤具有更高水平的MET表达。这些结果将p5缺失和β-连环蛋白激活与三阴性癌症中的干细胞调节和肿瘤发生联系起来，并突出了Met信号在维持癌症干细胞特性中的作用，揭示了靶向治疗的新线索。
