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

Johanna Rieckhoff,Britta Riepen,Sandra Classen,Alexandra Zielinski,Ann Christin Parplys,Harriet Wikman,Kai Rothkamm,Kerstin Borgmann,Cordula Petersen,Felix Meyer

doi:10.3390/cancers12102809

Johanna Rieckhoff, Britta Riepen + Show 8 more

Open Access

https://doi.org/10.3390/cancers12102809

Copy DOI

Abstract

Simple SummaryThe poor prognosis of patients with TNBC have fostered a major effort to identify more patients who would benefit from targeted therapies. Here we recognize PTEN as a potential CIN-causing gene in TNBC and consider PTEN-deficient TNBC for the treatment with PARP1 inhibitors due to the protective role of PTEN during DNA replication.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.

Highlights

Chromosomal instability (CIN) is a type of genomic instability that is defined by the loss or rearrangement of chromosomes that classifies numerical CIN or structural CIN [1]
To investigate whether Phosphatase and Tensin homolog (PTEN) plays a role in the maintenance of CIN in triple-negative breast cancer (TNBC), an in silico analysis of messenger RNA expression (mRNA) expression data from TNBC tumors, previously determined in the Metabric study, was performed [18]
Western blot data showed no expression of PTEN in BT549, intermediate expression in MDA231 and low expression among the three other TNBC cell lines (Figure 1b)

Summary

Introduction

Chromosomal instability (CIN) is a type of genomic instability that is defined by the loss or rearrangement of chromosomes that classifies numerical CIN or structural CIN [1]. DNA replication are known to cause CIN [2,3,4]. The spectrum of gene alterations and mutations that cause CIN is only partially known, but insights would be beneficial for the treatment of tumors with high CIN (CIN+ ). Phosphatase and Tensin homolog (PTEN) is an important tumor-suppressor gene frequently mutated or deleted in human cancer. PTEN is known to play an important role in antagonizing the PI3K-AKT pathway in the cytoplasm [6]. Nuclear PTEN is involved in genome maintenance pathways [5]

Objectives

Methods

Results

Conclusion