Exploiting Chromosomal Instability of PTEN-Deficient Triple-Negative Breast Cancer Cell Lines for the Sensitization Against PARP1 Inhibition in a Replication-Dependent Manner

Abstract

Chromosomal instability (CIN) is an emerging hallmark of cancer and its role in therapeutic responses has been increasingly attracting the attention of the research community. To target the vulnerability of tumors with high CIN, it is important to identify the genes and mechanisms involved in the maintenance of CIN. In our work, we recognize the tumor suppressor gene Phosphatase and Tensin homolog (PTEN) as a potential gene causing CIN in triple-negative breast cancer (TNBC) and show that TNBC with low expression levels of PTEN can be sensitized for the treatment with poly-(ADP-ribose)-polymerase 1 (PARP1) inhibitors, independent of Breast Cancer (BRCA) mutations or a BRCA-like phenotype. In silico analysis of mRNA expression data from 200 TNBC patients revealed low expression of PTEN in tumors with a high CIN70 score. Western blot analysis of TNBC cell lines confirm lower protein expression of PTEN compared to non TNBC cell lines. Further, PTEN-deficient cell lines showed cellular sensitivity towards PARP1 inhibition treatment. DNA fiber assays and examination of chromatin bound protein fractions indicate a protective role of PTEN at stalled replication forks. In this study, we recognize PTEN as a potential CIN-causing gene in TNBC and identify its important role in the replication processes.

DNA Damage Response during Replication Correlates with CIN70 Score and Determines Survival in HNSCC Patients

“…To test the hypothesis that therapy resistance manifests during S-phase, DNA replication processes in the two most resistant and most sensitive cell lines were studied in detail [ 19 , 20 , 21 , 22 ]. The focus was on both the protection of the already replicated DNA strand (fork protection) and the restart of replication after damage repair (fork recovery) ( Figure 4 A,B).…”

“…Replication is mainly controlled by activation of the kinase CHK1 through phosphorylation [ 19 , 20 , 21 ]. To study CHK1 activation specifically in S phase, UV irradiation was used [ 22 ] ( Figure 4 F).…”

“…Fibers were examined using an Axioplan 2 fluorescence microscope (Zeiss, Oberkochen, Germany). CldU and IdU tracks were measured using ImageJ (version 1.48, Wayne Rasband, NIH, USA) [ 19 , 20 , 21 , 22 , 48 ]. At least 300 forks were analyzed.…”

Development and evaluation of poly adenosine 5′‐diphosphate‐ribose polymerase 1 immobilization‐based receptor chromatography

“…The PARP1 inhibitors, iniparib and olaparib, are effective for the treatment of triple negative breast cancer (TNBC) and BRCA‐associated BC, which take up ∼40% of the currently diagnosed BC [12]. It is demonstrated that PARP1 inhibitors could treat BC through the crosstalk between NF‐κB, ERK, JNK, or other signaling pathways and PARP1 [13,14]. Many of the pathways are similar to YHD for the treatment of BC.…”

Up to your NEK2 in CIN

“…However, outcomes are less favorable for those patients with residual disease [ 9 ]. Emerging data demonstrate that TNBCs harbor increased levels of unstable aneuploidy, mitotic errors, and chromosomal instability (CIN), and together these are responsible for the heterogeneity and therapeutic resistance observed in this disease [ 10 – 12 ]. While low/moderate level CIN promotes cancer cell fitness, allowing cells to adapt and survive chromosomal insults and environmental stress, the excessive rates of CIN induced by taxanes causes excessive, unrecoverable damage [ 12 ].…”