Cell cycle regulation accounts for variability in Ki-67 expression levels

Sobecki, M.; Mrouj, K.; Colinge, J.; Gerbe, F.; Jay, P.; Krasinska, L.; Dulic, V.; Fisher, D.

Cancer Res

2017 May 15 / vol 77(10) / pages 2722-2734


The cell proliferation antigen Ki-67 is widely used in cancer histopathology, but estimations of Ki-67 expression levels are inconsistent and understanding of its regulation is limited. Here we show that cell cycle regulation underlies variable Ki-67 expression in all situations analyzed, including non-transformed human cells, normal mouse intestinal epithelia and adenomas, human cancer cell lines with or without drug treatments, and human breast and colon cancers. In normal cells, Ki-67 was a late marker of cell cycle entry; Ki-67 mRNA oscillated with highest levels in G2 while protein levels increased throughout the cell cycle, peaking in mitosis. Inhibition of CDK4/CDK6 revealed proteasome-mediated Ki-67 degradation in G1. After cell cycle exit, low-level Ki-67 expression persisted but was undetectable in fully quiescent differentiated cells or senescent cells. CDK4/CDK6 inhibition in vitro and in tumors in mice caused G1 cell cycle arrest and eliminated Ki-67 mRNA in RB1-positive cells but had no effect in RB1-negative cells, which continued to proliferate and express Ki-67. Thus, Ki-67 expression varies due to cell cycle regulation, but it remains a reliable readout for effects of CDK4/CDK6 inhibitors on cell proliferation.

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1538-7445 (Electronic) 0008-5472 (Linking)

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