DNA repair, genome stability and cancer: a historical perspective

Jeggo, Penny A.; Pearl, Laurence H.; Carr, Antony

doi:10.1038/nrc.2015.4

Cited by 646 publications

(515 citation statements)

References 92 publications

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“…15 Mechanistic studies unveiled that the Hippo-DDR cooperation promotes replication fork stability, cell-cycle checkpoint activation and DNA repair. 14 On this premise, we hypothesized that the expression of phosphorylated MST1/2 (pMST1/2) and LATS1/2 (pLATS1/2) may be associated with the efficacy of neoadjuvant therapy (NAT) in BC patients in a context-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

Expression of phosphorylated Hippo pathway kinases (MST1/2 and LATS1/2) in HER2-positive and triple-negative breast cancer patients treated with neoadjuvant therapy

Ercolani¹,

Benedetto²,

Terrenato

et al. 2017

Cancer Biology & Therapy

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The Hippo kinases MST1/2 and LATS1/2 inhibit the oncoproteins TAZ/YAP and regulate T cell function. Hippo kinases also cooperate with the ATR-Chk1 and ATM-Chk2 pathways, central orchestrators of the DNA damage response (DDR). We hypothesized that MST1/2 and LATS1/2 localization differently impacts the efficacy of neoadjuvant therapy (NAT) in breast cancer, being protective when expressed in the cytoplasm of tumor cells and in tumor-infiltrating lymphocytes, whereas representing molecular determinants of chemoresistance when present in the nucleus as a consequence of their cooperation with the DDR. Diagnostic biopsies from 57 HER2-positive and triple-negative breast cancer patients treated with NAT were immunostained for evaluating the expression of phosphorylated MST1/2 (pMST1/2) and LATS1/2 (pLATS1/2) in tumor-infiltrating lymphocytes (TILs) and in cancer cells. TAZ and Chk1 immunostaining was exploited for investigating subcellular compartment-dependent activity of Hippo kinases. Nuclear pMST1/2 (pMST1/2 nuc ) expression was significantly associated with nuclear expression of Chk1 (p D 0.046), whereas cytoplasmic pMST1/2 (pMST1/2 cyt ) expression was marginally associated with cytoplasmic TAZ staining (p D 0.053). Patients whose tumors expressed pMST1/2 nuc were at increased risk of residual disease after NAT (pCR ypT0/is ypN0: OR 4.91, 95%CI: 1.57-15.30; pCR ypT0 ypN0: OR 3.59, 95%CI 1.14-11.34). Conversely, exclusive cytoplasmic localization of pMST1/2 (pMST1/2 cyt )seemed to be a protective factor (pCR ypT0/is ypN0: OR 0.34, 95%CI: 0.11-1.00; pCR ypT0 ypN0: OR 0.31, 95%CI 0.10-0.93). The subcellular localization-dependent significance of pMST1/2 expression suggests their involvement in different molecular networks with opposite impact on NAT efficacy. Larger studies are warranted to confirm these novel findings.KEYWORDS HER2-positive breast cancer; Hippo pathway; LATS 1/2; MST1/2; triple-negative breast cancer

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Section: Introductionmentioning

confidence: 99%

Expression of phosphorylated Hippo pathway kinases (MST1/2 and LATS1/2) in HER2-positive and triple-negative breast cancer patients treated with neoadjuvant therapy

Ercolani¹,

Benedetto²,

Terrenato

et al. 2017

Cancer Biology & Therapy

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“…Cancer cells generally grow more rapidly than normal cells, and the rate of DNA replication is particularly elevated in these cells (19). DNA is unstable in its replication process (20), and thus RID-B may more easily bind to DNA in cancer cells than in normal cells, causing cancer cell death. Taken together, it may be proposed that cancer cells are more sensitive to RIDs compared with normal cells.…”

Section: Discussionmentioning

confidence: 99%

Anti‑proliferative effect of ridaifen‑B on hepatoma cells

et al. 2018

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Abstract. Ridaifens (RIDs), a novel series of tamoxifen derivatives, exhibit a potent growth-inhibitory effect against numerous tumor cells regardless of the expression of estrogen receptors, and are thus promising candidates as novel anti-tumor drugs. RID-B is a first generation RIDs, and inhibits the proliferation of several tumor cell lines. However, the potentially growth inhibitory effect of RID-B against hepatoma cells, and the detailed mechanism underlying RID-B-mediated tumor cell death remain to be elucidated. The purpose of the current study was to evaluate the anti-proliferative effect of RID-B against hepatoma cells. The anti-proliferative effect of RID-B against human hepatoma Huh-7 cells was investigated by cell proliferation assay using WST-1 reagent, and caspase-3 activity was evaluated by using specific fluorescent substrate. In addition, DNA fragmentation in Huh-7 cells induced by RID-B was estimated by terminal deoxynucleotidyl transferase dUTP nick-end labelling assay, and binding of RID-B to double-stranded DNA was confirmed by mass spectrometry. RID-B (0.5, 1 and 2 µM) inhibited the growth of Huh-7 cells, seemingly dose-dependently, but did not inhibit the growth of normal primary rat hepatocytes in the same concentration range. Furthermore, the caspase-3 activity of Huh-7 cells was increased by RID-B (0.5 and 5 µM), and the anti-proliferative effect of RID-B (1 µM) on Huh-7 cells was partially suppressed by the addition of the caspase inhibitor, Z-VAD-FMK. Additionally, RID-B (10 µM) directly bound to double-stranded DNA, and the addition of DNA suppressed RID-B-mediated cell growth inhibition and DNA fragmentation in Huh-7 cells. From these data, it may be concluded that RID-B inhibited cell growth and induced apoptosis via activating caspase-3 and binding to DNA directly, leading to DNA fragmentation in hepatoma cells.

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“…Consistent with this theory, acquisition of 'loss of function' mutations in these checkpoint proteins, most commonly p53, is associated with malignant progression. While not a universal phenomenon, the concept of the DDR as an 'anti-cancer barrier' is a plausible explanation for the high prevalence of DDR dysfunction in malignant disease, and identifies a family of attractive therapeutic targets (reviewed in [7]). …”

Section: Introductionmentioning

confidence: 99%

Science in Focus: Combining Radiotherapy with Inhibitors of the DNA Damage Response

Chalmers

2016

Clinical Oncology

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DNA repair, genome stability and cancer: a historical perspective

Cited by 646 publications

References 92 publications

Expression of phosphorylated Hippo pathway kinases (MST1/2 and LATS1/2) in HER2-positive and triple-negative breast cancer patients treated with neoadjuvant therapy

Expression of phosphorylated Hippo pathway kinases (MST1/2 and LATS1/2) in HER2-positive and triple-negative breast cancer patients treated with neoadjuvant therapy

Anti‑proliferative effect of ridaifen‑B on hepatoma cells

Science in Focus: Combining Radiotherapy with Inhibitors of the DNA Damage Response

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