title: Cell-Cycle Regulation Accounts for Variability in Ki-67 Expression Levels.
abstract: 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 nontransformed 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 G2while protein levels increased throughout the cell cycle, peaking in mitosis. Inhibition of CDK4/CDK6 revealed proteasome-mediated Ki-67 degradation in G1After cell-cycle exit, low-level Ki-67 expression persisted but was undetectable in fully quiescent differentiated cells or senescent cells. CDK4/CDK6 inhibitionin vitroand in tumors in mice caused G1cell-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.Cancer Res; 77(10); 2722-34. ©2017 AACR.
authors.affiliation: IGMM, CNRS Univ. Montpellier, Montpellier, France.
authors.forename: Michal
authors.initials: M
authors.lastname: Sobecki
authors.affiliation: IGMM, CNRS Univ. Montpellier, Montpellier, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Mrouj
authors.affiliation: IRCM, INSERM ICM, Univ. Montpellier, Montpellier, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Colinge
authors.affiliation: IGF, CNRS, INSERM, Univ. Montpellier, Montpellier, France.
authors.forename: François
authors.initials: F
authors.lastname: Gerbe
authors.affiliation: IGF, CNRS, INSERM, Univ. Montpellier, Montpellier, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Jay
authors.affiliation: IGMM, CNRS Univ. Montpellier, Montpellier, France.
authors.forename: Liliana
authors.initials: L
authors.lastname: Krasinska
authors.affiliation: IGMM, CNRS Univ. Montpellier, Montpellier, France.
authors.forename: Vjekoslav
authors.initials: V
authors.lastname: Dulic
authors.affiliation: IGMM, CNRS Univ. Montpellier, Montpellier, France. daniel.fisher@igmm.cnrs.fr.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fisher
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015415:Biomarkers; D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D016000:Cluster Analysis; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D019394:Ki-67 Antigen / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D019394:Ki-67 Antigen