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/b-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 CK2a in the mammary gland. We ®nd that CK2 is highly expressed in human breast tumor specimens and in carcinogeninduced rat mammary tumors. Overexpression of CK2a 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-CK2a transgenic mice develop mammary adenocarcinomas at a median of 23 months of age, often associated with Wnt pathway activation, as evidenced by upregulation of b-catenin protein. NF-kB 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. Oncogene (2001) 20, 3247 ± 3257.

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Protein kinase CK2 is a ubiquitous serine/threonine kinase involved in many biological processes. It is overexpressed in many malignancies including rodent and human breast cancer, and is up-regulated in Wnt-transfected mammary epithelial cells, where it can be found in a complex with dishevelled and ␤-catenin. ␤-Catenin is a substrate for CK2 and inhibition of CK2 reduces levels of ␤-catenin and dishevelled. Here we report that inhibition of CK2 using pharmacologic agents or expression of kinase inactive subunits reduces ␤-catenindependent transcription and protein levels in a proteasome-dependent fashion. The major region of phosphorylation of ␤-catenin by CK2 is the central armadillo repeat domain, where carrier proteins like axin and the adenomatous polyposis coli gene product APC interact with ␤-catenin. The major CK2 phosphorylation site in this domain is Thr 393 , a solvent-accessible residue in a key hinge region of the molecule. Mutation of this single amino acid reduces ␤-catenin phosphorylation, cotranscriptional activity, and stability. Thus, CK2 is a positive regulator of Wnt signaling through phosphorylation of ␤-catenin at Thr 393 , leading to proteasome resistance and increased protein and co-transcriptional activity.Protein kinase CK2 is ubiquitously expressed in both the cytoplasm and nucleus of eukaryotic cells. It is highly conserved through evolution; mammalian CK2 can substitute for the yeast enzyme (1). CK2 functions as a tetramer assembled by homodimerization of two regulatory ␤ subunits followed by recruitment of two catalytic subunits (␣ or ␣Ј) (2-4). The catalytic subunits are highly homologous to each other but are encoded by different genes (5). Activity is regulated by the ␤ subunit, which confers some of the substrate specificity (6). In S. cerevisiae, deletion of either of the catalytic subunits results in a normal phenotype, but deletion of both leads to growth arrest (7). In mammals, the ␣Ј subunit is required for normal male germ cell development (8).CK2 is not known to be regulated by second messengers, but its activity is enhanced by polyamines and polylysines (9 -11) and inhibited by apigenin (chrysin) (12), 6-dichloro-1-␤-D-ribofuranosylbenzimidazole (13), and emodin (14). Biochemically, CK2 is unusual in that it is one of the few kinases that can efficiently utilize either ATP or GTP as the phosphoryl donor (15), a property that is very useful experimentally to identify its activity.CK2 phosphorylates serine or threonine in acidic domains, with S/TXXD/E being the canonical motif (16 -19). CK2 regulates many fundamental cellular processes. Of particular interest with respect to cancer biology, CK2 phosphorylates many transcription factors, proto-oncoproteins, and tumor suppressor proteins including c-Myc (20), Max (21), p53 (22), Mdm-2 (23), c-Jun (24), SV40 large T antigen (25), and others.CK2 phosphorylation can regulate DNA binding, e.g. for c-Jun (24) or Max (21) or nuclear translocation, e.g. for SV40 large T antigen (25). However, one of the important functions of CK2...