Vesuna Farhad, Bergman Yehudit, Raman Venu
Division of Cancer Imaging Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
BMC Cancer. 2017 Jan 13;17(1):52. doi: 10.1186/s12885-016-3033-3.
The basic helix-loop-helix transcription factor TWIST1 (Twist) is involved in embryonic cell lineage determination and mesodermal differentiation. There is evidence to indicate that Twist expression plays a role in breast tumor formation and metastasis, but the role of Twist in dysregulating pathways that drive the metastatic cascade is unclear. Moreover, many of the genes and pathways dysregulated by Twist in cell lines and mouse models have not been validated against data obtained from larger, independant datasets of breast cancer patients.
We over-expressed the human Twist gene in non-metastatic MCF-7 breast cancer cells to generate the estrogen-independent metastatic breast cancer cell line MCF-7/Twist. These cells were inoculated in the mammary fat pad of female severe compromised immunodeficient mice, which subsequently formed xenograft tumors that metastasized to the lungs. Microarray data was collected from both in vitro (MCF-7 and MCF-7/Twist cell lines) and in vivo (primary tumors and lung metastases) models of Twist expression. Our data was compared to several gene datasets of various subtypes, classes, and grades of human breast cancers.
Our data establishes a Twist over-expressing mouse model of breast cancer, which metastasizes to the lung and replicates some of the ontogeny of human breast cancer progression. Gene profiling data, following Twist expression, exhibited novel metastasis driver genes as well as cellular maintenance genes that were synonymous with the metastatic process. We demonstrated that the genes and pathways altered in the transgenic cell line and metastatic animal models parallel many of the dysregulated gene pathways observed in human breast cancers.
Analogous gene expression patterns were observed in both in vitro and in vivo Twist preclinical models of breast cancer metastasis and breast cancer patient datasets supporting the functional role of Twist in promoting breast cancer metastasis. The data suggests that genetic dysregulation of Twist at the cellular level drives alterations in gene pathways in the Twist metastatic mouse model which are comparable to changes seen in human breast cancers. Lastly, we have identified novel genes and pathways that could be further investigated as targets for drugs to treat metastatic breast cancer.
碱性螺旋-环-螺旋转录因子TWIST1（Twist）参与胚胎细胞谱系的确定和中胚层分化。有证据表明Twist表达在乳腺肿瘤的形成和转移中起作用，但Twist在驱动转移级联反应的失调途径中的作用尚不清楚。此外，Twist在细胞系和小鼠模型中失调的许多基因和途径尚未根据从更大的、独立的乳腺癌患者数据集中获得的数据进行验证。
我们在非转移性MCF-7乳腺癌细胞中过表达人Twist基因，以生成雌激素非依赖性转移性乳腺癌细胞系MCF-7/Twist。将这些细胞接种到雌性严重免疫缺陷小鼠的乳腺脂肪垫中，随后形成转移至肺部的异种移植肿瘤。从Twist表达的体外（MCF-7和MCF-7/Twist细胞系）和体内（原发性肿瘤和肺转移灶）模型收集微阵列数据。我们的数据与各种亚型、类别和分级的人类乳腺癌的几个基因数据集进行了比较。
我们的数据建立了一种Twist过表达的乳腺癌小鼠模型，该模型可转移至肺部并复制了人类乳腺癌进展的一些个体发生过程。Twist表达后的基因谱数据显示出与转移过程同义的新型转移驱动基因以及细胞维持基因。我们证明，转基因细胞系和转移性动物模型中改变的基因和途径与人类乳腺癌中观察到的许多失调基因途径相似。
在乳腺癌转移的体外和体内Twist临床前模型以及乳腺癌患者数据集中观察到类似的基因表达模式，支持Twist在促进乳腺癌转移中的功能作用。数据表明，细胞水平上Twist的基因失调驱动了Twist转移性小鼠模型中基因途径的改变，这与人类乳腺癌中看到的变化相当。最后，我们确定了新的基因和途径，可作为治疗转移性乳腺癌的药物靶点进行进一步研究。
