Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Oncogene. 2013 Apr 25;32(17):2121-30. doi: 10.1038/onc.2012.328. Epub 2012 Oct 8.
The three RUNX family members are lineage specific master regulators, which also have important, context-dependent roles in carcinogenesis as either tumor suppressors or oncogenes. Here we review evidence for such roles in breast cancer (BCa). RUNX1, the predominant RUNX family member in breast epithelial cells, has a tumor suppressor role reflected by many somatic mutations found in primary tumor biopsies. The classical tumor suppressor gene RUNX3 does not consist of such a mutation hot spot, but it too seems to inhibit BCa; it is often inactivated in human BCa tumors and its haploinsufficiency in mice leads to spontaneous BCa development. The tumor suppressor activities of RUNX1 and RUNX3 are mediated in part by antagonism of estrogen signaling, a feature recently attributed to RUNX2 as well. Paradoxically, however RUNX2, a master osteoblast regulator, has been implicated in various aspects of metastasis in general and bone metastasis in particular. Reciprocating the anti-estrogenic tumor suppressor activity of RUNX proteins, inhibition of RUNX2 by estrogens may help explain their context-dependent anti-metastatic roles. Such roles are reserved to non-osseous metastasis, because ERα is associated with increased, not decreased skeletal dissemination of BCa cells. Finally, based on diverse expression patterns in BCa subtypes, the successful use of future RUNX-based therapies will most likely require careful patient selection.
RUNX 家族的三个成员是谱系特异性的主调控因子，它们在致癌作用中也具有重要的、依赖于背景的作用，既可以作为肿瘤抑制因子，也可以作为癌基因。在这里，我们回顾了这些作用在乳腺癌（BCa）中的证据。RUNX1 是乳腺上皮细胞中主要的 RUNX 家族成员，其具有肿瘤抑制作用，这反映在原发性肿瘤活检中发现的许多体细胞突变中。经典的肿瘤抑制基因 RUNX3 没有这样的突变热点，但它似乎也抑制 BCa；它在人类 BCa 肿瘤中经常失活，其在小鼠中的单倍不足导致自发性 BCa 发展。RUNX1 和 RUNX3 的肿瘤抑制活性部分是通过拮抗雌激素信号来介导的，最近也归因于 RUNX2。然而，具有矛盾的是，作为主要成骨细胞调节剂的 RUNX2 已被牵连到转移的各个方面，特别是骨转移。与 RUNX 蛋白的抗雌激素肿瘤抑制活性相反，雌激素对 RUNX2 的抑制作用可能有助于解释其依赖背景的抗转移作用。这种作用仅限于非骨转移，因为 ERα 与 BCa 细胞的骨骼扩散增加而不是减少有关。最后，基于 BCa 亚型中的不同表达模式，未来基于 RUNX 的治疗的成功应用很可能需要仔细的患者选择。
