Abstract
PurposePhosphate and tensin homolog (PTEN), a negative regulator of PI3K signaling, is involved in DNA repair. ATR is a key sensor of DNA damage and replication stress. We evaluated whether ATR signaling has clinical significance and could be targeted by synthetic lethality in PTEN-deficient triple-negative breast cancer (TNBC).MethodsPTEN, ATR and pCHK1Ser345 protein level was evaluated in 1650 human breast cancers. ATR blockade by VE-821 was investigated in PTEN-proficient- (MDA-MB-231) and PTEN-deficient (BT-549, MDA-MB-468) TNBC cell lines. Functional studies included DNA repair expression profiling, MTS cell-proliferation assay, FACS (cell cycle progression & γH2AX accumulation) and FITC-annexin V flow cytometry analysis.ResultsLow nuclear PTEN was associated with higher grade, pleomorphism, de-differentiation, higher mitotic index, larger tumour size, ER negativity, and shorter survival (p values < 0.05). In tumours with low nuclear PTEN, high ATR and/or high pCHK1ser345 level was also linked to higher grade, larger tumour size and poor survival (all p values < 0.05). VE-821 was selectively toxic in PTEN-deficient TNBC cells and resulted in accumulation of double-strand DNA breaks, cell cycle arrest, and increased apoptosis.ConclusionATR signalling adversely impact survival in PTEN-deficient breast cancers. ATR inhibition is synthetically lethal in PTEN-deficient TNBC cells.
Highlights
Phosphate and tensin homolog (PTEN) is a key tumor suppressor [5, 7, 14, 22]
The loss of nuclear PTEN expression was observed in 508/811 (62.6%) tumours compared with 303/811 (37.4%)
We provide the first clinical evidence that Ataxia telangiectasia-mutatedand Rad3-related protein (ATR) signaling could have adverse impact on survival in PTEN-deficient breast cancers
Summary
Phosphate and tensin homolog (PTEN) is a key tumor suppressor [5, 7, 14, 22]. Mutations in PTEN have been reported in several tumours including brain, prostrate, melanoma, endometrial and breast cancers. Nuclear PTEN has been shown to have roles in DNA repair [5, 7, 14, 22]. Activated ATR in turn phosphorylates Chk at S er345 and S er317, as well as several other target proteins involved in homologous recombination repair and. Phosphorylation of Chk at Ser345 (pChk1) leads to its activation which further coordinates cell cycle progression and DNA repair [9, 10, 19, 20]. We provide evidence that ATR and pChk expression in of PTEN-deficient breast cancer adversely impact on survival. ATR inhibition is synthetically lethal in PTEN-deficient TNBC cells implying a promising personalized therapy approach in breast cancers
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