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.

Protein kinase CK2 (formerly casein kinase II) is a highly conserved and ubiquitous serine/threonine kinase that is composed of two catalytic subunits (CK2␣ and/or CK2␣) and two CK2␤ regulatory subunits. CK2 has many substrates in cells, and key roles in yeast cell physiology have been uncovered by introducing subunit mutations. Gene-targeting experiments have demonstrated that in mice, the CK2␤ gene is required for early embryonic development, while the CK2␣ subunit appears to be essential only for normal spermatogenesis. We have used homologous recombination to disrupt the CK2␣ gene in the mouse germ line. Embryos lacking CK2␣ have a marked reduction in CK2 activity in spite of the presence of the CK2␣ subunit. CK2␣ ؊/؊ embryos die in mid-gestation, with abnormalities including open neural tubes and reductions in the branchial arches. Defects in the formation of the heart lead to hydrops fetalis and are likely the cause of embryonic lethality. Thus, CK2␣ appears to play an essential and uncompensated role in mammalian development.