Aberrant APOBEC3B Expression in Breast Cancer Is Linked to Proliferation and Cell Cycle Phase

被引:5
|
作者
Roelofs, Pieter A. A. [1 ,2 ,3 ]
Timmermans, Mieke A. M. [4 ]
Stefanovska, Bojana [2 ,3 ,5 ,6 ]
den Boestert, Myrthe A. A. [4 ]
van den Borne, Amber W. M. [1 ]
Balcioglu, Hayri E. E. [4 ]
Trapman, Anita M. M. [4 ]
Harris, Reuben S. S. [2 ,3 ,5 ,6 ]
Martens, John W. M. [4 ]
Span, Paul N. N. [1 ,6 ]
机构
[1] Radboud Univ Nijmegen, Med Ctr, Dept Radiat Oncol, Radiotherapy & OncoImmunol Lab, NL-6525 GA Nijmegen, Netherlands
[2] Univ Minnesota, Inst Mol Virol, Masonic Canc Ctr, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA
[3] Univ Minnesota, Ctr Genome Engn, Minneapolis, MN 55455 USA
[4] Erasmus MC, Erasmus Univ Med Ctr, Canc Inst, Dept Med Oncol, NL-3000 CA Rotterdam, Netherlands
[5] Univ Texas Hlth San Antonio, Dept Biochem & Struct Biol, San Antonio, TX 78229 USA
[6] Univ Texas Hlth San Antonio, Howard Hughes Med Inst, San Antonio, TX 78229 USA
关键词
APOBEC3B; cell cycle; transcription; G(2)/M; RB/E2F pathway; PKC/ncNF-?B pathway; MUTATIONAL SIGNATURES; DEAMINASE APOBEC3B; INHIBITION; GENES; TUMOR;
D O I
10.3390/cells12081185
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
APOBEC3B (A3B) is aberrantly overexpressed in a subset of breast cancers, where it associates with advanced disease, poor prognosis, and treatment resistance, yet the causes of A3B dysregulation in breast cancer remain unclear. Here, A3B mRNA and protein expression levels were quantified in different cell lines and breast tumors and related to cell cycle markers using RT-qPCR and multiplex immunofluorescence imaging. The inducibility of A3B expression during the cell cycle was additionally addressed after cell cycle synchronization with multiple methods. First, we found that A3B protein levels within cell lines and tumors are heterogeneous and associate strongly with the proliferation marker Cyclin B1 characteristic of the G(2)/M phase of the cell cycle. Second, in multiple breast cancer cell lines with high A3B, expression levels were observed to oscillate throughout the cell cycle and again associate with Cyclin B1. Third, induction of A3B expression is potently repressed throughout G(0)/early G(1), likely by RB/E2F pathway effector proteins. Fourth, in cells with low A3B, induction of A3B through the PKC/ncNF-?B pathway occurs predominantly in actively proliferating cells and is largely absent in cells arrested in G(0). Altogether, these results support a model in which dysregulated A3B overexpression in breast cancer is the cumulative result of proliferation-associated relief from repression with concomitant pathway activation during the G(2)/M phase of the cell cycle.
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页数:18
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