Landesman-Bollag E, Romieu-Mourez R, Song D H, Sonenshein G E, Cardiff R D, Seldin D C
Department of Medicine, Boston Medical Center, Boston, Massachusetts, MA 02118-2394, USA.
Oncogene. 2001 May 31;20(25):3247-57. doi: 10.1038/sj.onc.1204411.
Protein kinase CK2 is a ubiquitous and evolutionarily conserved serine/threonine kinase that is upregulated in many human cancers and can serve as an oncogene in lymphocytes. Recently, we have demonstrated that CK2 potentiates Wnt/beta-catenin signaling in mammary epithelial cells. To determine whether CK2 overexpression contributes to mammary tumorigenesis, we have performed comparative studies of human and rat breast cancer specimens and we have engineered transgenic mice with dysregulated expression of CK2alpha in the mammary gland. We find that CK2 is highly expressed in human breast tumor specimens and in carcinogen-induced rat mammary tumors. Overexpression of CK2alpha in the mammary gland of transgenic mice, under control of the MMTV-LTR, causes hyperplasia and dysplasia of the female mammary gland. Thirty per cent of the female MMTV-CK2alpha transgenic mice develop mammary adenocarcinomas at a median of 23 months of age, often associated with Wnt pathway activation, as evidenced by upregulation of beta-catenin protein. NF-kappaB activation and upregulation of c-Myc also occur frequently. Thus, in mice, rats, and humans, dysregulated expression of CK2 is associated with and is capable of contributing to mammary tumorigenesis. Targeted inhibition of CK2 could be useful in the treatment of breast cancer.
蛋白激酶CK2是一种广泛存在且在进化上保守的丝氨酸/苏氨酸激酶，在许多人类癌症中上调，并且在淋巴细胞中可作为一种癌基因。最近，我们已经证明CK2在乳腺上皮细胞中增强Wnt/β-连环蛋白信号传导。为了确定CK2的过表达是否有助于乳腺肿瘤发生，我们对人类和大鼠乳腺癌标本进行了比较研究，并构建了乳腺中CK2α表达失调的转基因小鼠。我们发现CK2在人类乳腺肿瘤标本和致癌物诱导的大鼠乳腺肿瘤中高度表达。在MMTV-LTR的控制下，转基因小鼠乳腺中CK2α的过表达导致雌性乳腺增生和发育异常。30%的雌性MMTV-CK2α转基因小鼠在23个月龄的中位数时发生乳腺腺癌，通常与Wnt途径激活相关，β-连环蛋白蛋白上调证明了这一点。NF-κB激活和c-Myc上调也经常发生。因此，在小鼠、大鼠和人类中，CK2的表达失调与乳腺肿瘤发生相关并且能够促成乳腺肿瘤发生。对CK2的靶向抑制可能对乳腺癌治疗有用。
