Abstract
Triple‐negative breast cancer (TNBC) is a malignancy that currently lacks targeted therapies. The majority of TNBCs can be characterized as basal‐like and has an expression profile enriched with genes involved in DNA damage repair and checkpoint response. Here, we report that TNBC cells are under replication stress and are constantly generating DNA double‐strand breaks, which is not seen in non‐TNBC cells. Consequently, we found that RECQL5, which encodes a RecQ family DNA helicase involved in many aspects of DNA metabolism including replication and repair, was essential for TNBC cells to survive and proliferate in vitro and in vivo. Compromising RECQL5 function in TNBC cells results in persistence of DNA damage, G2 arrest, and ultimately, cessation of proliferation. Our results suggest RECQL5 may be a potential therapeutic target for TNBC.
Highlights
Genome instability, resulted from defects in DNA metabolism including replication and repair, is a hallmark of cancer.[1]
Through analyzing the Cancer Genome Atlas (TCGA) breast cancer RNA‐Seq data sets,[28] we found that RECQL5 mRNA levels were modestly elevated in two breast tumor subtypes, luminal and triple‐negative compared with normal breast tissue (Figure S5C)
Among various types of breast cancers, Triple‐negative breast cancer (TNBC) is unique, in its hormone receptor status and in its association with high levels of endogenous DNA damage manifested by a gene expression profile enriched with DNA damage response genes[6] and by histological observation in clinical samples.[30]
Summary
Genome instability, resulted from defects in DNA metabolism including replication and repair, is a hallmark of cancer.[1]. The majority of TNBCs can be characterized as basal‐like[4] and have an expression profile enriched with genes involved in DNA damage checkpoint response.[5,6] More than 80% of breast cancer patients with a hereditary BRCA1 mutation are assigned to TNBC subtype.[7] Some sporadic TNBCs show similar characteristics with BRCA1‐mutant tumors Together, they are referred as BRCAness.[8] While targeted therapies are available for other subtypes of breast cancer, TNBCs currently lack targeted therapies (except BRCA1 mutated ones) and their treatment relies heavily on broad cytotoxic chemotherapeutic agents.[9]. Together with the observation that RECQL5 is dispensable in normal cells, our results suggest RECQL5 as a potential TNBC‐specific therapeutic target
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