Abstract
p27 is a key regulator of G1 to S phase progression. It inhibits cyclin E-Cdk2 in G0 and early G1 and promotes the assembly and activation of D-type cyclin-dependent kinases (cdks). While the p27 gene is rarely mutated in human cancers, p27 action is impaired in breast and other human cancers through accelerated p27 proteolysis, sequestration by cyclin D-cdks and p27 mislocalization in tumor cell cytoplasm. In cancers, reduced p27 protein reflects tumor de-differentiation and is associated with high histopathologic tumor grade. Reduced p27 is an indicator of poor patient outcome in primary human breast cancers. Following estrogen binding to the estrogen receptor (ER), p27is regulatedby therapidtransientER-mediatedactivationof Srcandsignaling pathways. This review will focus on mechanisms of p27 regulation in normal cells and howSrc activationmayderegulate p27 inbreastandotherhumancancers.The relevance of this pathway to antiestrogen therapy of breast cancers will also be reviewed.