Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):6991-6. doi: 10.1073/pnas.1303671110. Epub 2013 Apr 4.
Wnt signaling in mouse mammary development and tumorigenesis has been heavily studied and characterized, but its role in human breast cancer remains elusive. Although Wnt inhibitors are in early clinical development, it is unclear whether they will be of therapeutic benefit to breast cancer patients, and subsequently, to which ones. To address this, we generated a panel of Wnt reporting human breast cancer cell lines and identified a previously unrecognized enrichment for the ability to respond to Wnt in the basal B or claudin-low subtype, which has a poor prognosis and no available targeted therapies. By co-injecting Wnt3A expressing human mammary fibroblasts with human breast cancer cell lines into mouse mammary fat pads, we showed that elevated paracrine Wnt signaling was correlated with accelerated tumor growth. Using this heterotypic system and a dual lentiviral reporter system that enables simultaneous real-time measurement of both Wnt-responsive cells and bulk tumor cells, we analyzed the outcome of elevated Wnt signaling in patient-derived xenograft (PDX) models. Interestingly, the PDX models exhibited responses not observed in the cell lines analyzed. Exogenous WNT3A promoted tumor growth in one human epidermal growth factor receptor 2-overexpressing PDX line but inhibited growth in a second PDX line obtained from a patient with triple-negative breast cancer. Tumor suppression was associated with squamous differentiation in the latter. Thus, our work suggests that paracrine Wnt signaling can either fuel or repress the growth of human breast cancers depending on yet to be determined aspects of the molecular pathways they express.
Wnt 信号在小鼠乳腺发育和肿瘤发生中的作用已经得到了深入的研究和描述，但它在人类乳腺癌中的作用仍然难以捉摸。尽管 Wnt 抑制剂正在早期临床开发中，但尚不清楚它们是否对乳腺癌患者具有治疗益处，以及对哪些患者具有治疗益处。为了解决这个问题，我们生成了一组 Wnt 报告人源乳腺癌细胞系，并确定了以前未被认识到的对 Wnt 的反应能力在基底 B 或 Claudin-low 亚型中的富集，该亚型预后不良，且没有可用的靶向治疗方法。通过将表达 Wnt3A 的人乳腺成纤维细胞与人类乳腺癌细胞系共注射到小鼠乳腺脂肪垫中，我们表明，升高的旁分泌 Wnt 信号与肿瘤生长加速相关。使用这种异质系统和双慢病毒报告系统，我们能够同时实时测量 Wnt 反应性细胞和肿瘤细胞的总体，可以分析升高的 Wnt 信号在患者来源的异种移植（PDX）模型中的结果。有趣的是，PDX 模型表现出与分析的细胞系中观察到的不同的反应。外源性 WNT3A 促进了一个人表皮生长因子受体 2 过表达 PDX 系的肿瘤生长，但抑制了第二个 PDX 系的生长，该 PDX 系来自一名患有三阴性乳腺癌的患者。后者的肿瘤抑制与鳞状分化有关。因此，我们的工作表明，旁分泌 Wnt 信号可以根据它们表达的分子途径的尚未确定的方面来促进或抑制人类乳腺癌的生长。
