Decreased levels of the cell-cycle inhibitor p27^Kip1 protein: Prognostic implications in primary breast cancer

Abstract

Breast cancer is the second leading cause of cancer death in North American women. There is considerable need for reliable prognostic markers to assist clinicians in making management decisions. Although a variety of factors have been tested, only tumor stage, grade, size, hormone receptor status, and S-phase fraction are used on a routine basis¹. The cell cycle is governed by a family of cyclin-dependent kinases (cdks), which are regulated by associated cyclins and by phosphorylation². p27^Kip1, a cyclin-dependent kinase inhibitor, regulates progression from G₁ into S phase by binding and inhibiting cyclin/cdks^3,4. p27^Kip1 protein levels and/or activity are upregulated by growth inhibitory cytokines including transforming growth factor-β (TGF-β) and, thus, provide an important link between extracellular regulators and the cell cycle^5–7. Loss of p27^Kip1, a negative cell-cycle regulator, may contribute to oncogenesis and tumor progression. However, p27^Kip1 mutations in human tumors are extremely rare^8,9. We have demonstrated by immunohistochemistry that p27^Kip1 protein levels are reduced in primary breast cancers and that this is associated with tumor progression in both in situ and invasive lesions. This was confirmed by western analysis, reflected in increased G₁/S-phase cyclin-dependent kinase activities and shown to be regulated posttranscriptionally by in situ hybridization. Furthermore, on multivariate analysis, low p27^Kip1 is a predictor of reduced disease-free survival. This simple and reliable immunohistochemical assay may become a routine part of breast cancer evaluation and may influence patient management.