Cytoplasmic expression of p21CIP1/WAF1is correlated with IKKβ overexpression in human breast cancers

Proc Amer Assoc Cancer Res, Volume 47, 2006 4284 ABSTRACT Regulation of cytoplasmic p21CIP/WAF1 (p21) is of great clinical significance in cancer therapy due to its identification as an antiapoptosis factor, poor survival predictor as well as a drug-resistance inducer. A retrospective study of the immunohistochemical profiles of 128 human primary breast cancers showed that increased total and cytoplasmic p21 expression were highly associated with the expression of IκB kinase β (IKKβ), the major catalytic subunit of the IKK complex and another crucial player in tumorigenesis and drug resistance. The causal relationship study based on cultured cell lines confirmed that IKKβ overexpression did upregulate protein levels of total and cytoplasmic p21. Mechanistic investigation demonstrated that IKKβ increased p21 expression through upregulation of p21 mRNA level. Moreover, IKKβ was found to be able to upregulate Akt phosphorylation on Ser 473. This novel finding indicated that IKKβ could mediate cytoplasmic p21 accumulation via activation of its downstream target Akt, which was known to phosphorylate p21 on Thr 145 and lead to cytoplasmic localization of p21. Key words: p21; IKKβ; Akt; breast cancer