Browne Gillian, Taipaleenmäki Hanna, Bishop Nicole M, Madasu Sharath C, Shaw Leslie M, van Wijnen Andre J, Stein Janet L, Stein Gary S, Lian Jane B
Department of Biochemistry and Vermont Cancer Center, University of Vermont College of Medicine, Burlington, Vermont.
Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
J Cell Physiol. 2015 Oct;230(10):2522-32. doi: 10.1002/jcp.24989.
Runx1 is a transcription factor essential for definitive hematopoiesis, and genetic abnormalities in Runx1 cause leukemia. Runx1 is functionally promiscuous and acts as either an oncogene or tumor suppressor gene in certain epithelial cancers. Recent evidence suggests that Runx1 is an important factor in breast cancer, however, its role remains ambiguous. Here, we addressed whether Runx1 has a specific pathological role during breast cancer progression and show that Runx1 has an oncogenic function. We observed elevated Runx1 expression in a subset of human breast cancers. Furthermore, throughout the course of disease progression in a classical mouse model of breast cancer (i.e., the MMTV-PyMT transgenic model), Runx1 expression increases in the primary site (mammary gland) and is further upregulated in tumors and distal lung metastatic lesions. Ex vivo studies using tumor epithelial cells derived from these mice express significantly higher levels of Runx1 than normal mammary epithelial cells. The tumor cells exhibit increased rates of migration and invasion, indicative of an aggressive cancer phenotype. Inhibition of Runx1 expression using RNA interference significantly abrogates these cancer-relevant phenotypic characteristics. Importantly, our data establish that Runx1 contributes to murine mammary tumor development and malignancy and potentially represents a key disease-promoting and prognostic factor in human breast cancer progression and metastasis.
Runx1是确定性造血所必需的转录因子，Runx1的基因异常会导致白血病。Runx1功能多样，在某些上皮癌中既作为癌基因又作为肿瘤抑制基因发挥作用。最近的证据表明Runx1在乳腺癌中是一个重要因素，然而，其作用仍不明确。在此，我们探讨了Runx1在乳腺癌进展过程中是否具有特定的病理作用，并表明Runx1具有致癌功能。我们观察到在一部分人类乳腺癌中Runx1表达升高。此外，在经典的乳腺癌小鼠模型（即MMTV-PyMT转基因模型）的疾病进展过程中，Runx1在原发部位（乳腺）表达增加，并在肿瘤和远端肺转移病灶中进一步上调。使用源自这些小鼠的肿瘤上皮细胞进行的体外研究表明，Runx1的表达水平明显高于正常乳腺上皮细胞。肿瘤细胞表现出更高的迁移和侵袭率，表明具有侵袭性癌症表型。使用RNA干扰抑制Runx1表达可显著消除这些与癌症相关的表型特征。重要的是，我们的数据表明Runx1促进小鼠乳腺肿瘤的发生和恶性发展，并且可能是人类乳腺癌进展和转移中促进疾病发展和预后的关键因素。
