A Hormone–DNA Repair Circuit Governs the Response to Genotoxic Insult

Goodwin, Jonathan F.; Schiewer, Matthew J.; Dean, Jeffry L.; Schrecengost, Randy S.; Leeuw, Renée de; Han, Sumin; Ma, Teng; Den, Robert B.; Dicker, Adam P.; Feng, Felix Y.; Knudsen, Karen E.

doi:10.1158/2159-8290.cd-13-0108

Cited by 306 publications

(385 citation statements)

References 73 publications

(95 reference statements)

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“…Moreover, DNA-PKc stabilizes the MYC oncoprotein (11) and physically interacts with EGFR, which is frequently overexpressed in epithelial human tumors. A recent study revealed a positive-feedback loop between DNA-PKc and the androgen receptor (AR) in prostate cancer cells, providing a rationale for targeting DNA-PKc in AR-driven malignancies, particularly in advanced prostate cancer (24). In contrast with these findings, decreased DNA-PKc activity and expression has been reported in ovarian cancers, where this loss of expression was associated with tumor progression and metastasis (12).…”

Section: Emerging Evidence For the Role Of Constitutive Dna Damage Inmentioning

confidence: 99%

DNA Damage in Cancer Therapeutics: A Boon or a Curse?

2015

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Millions of DNA-damaging lesions occur every day in each cell of our bodies due to various stresses. The failure to detect and accurately repair these lesions can give rise to cells with high levels of endogenous DNA damage, deleterious mutations, or genomic aberrations. Such genomic instability can lead to the activation of specific signaling pathways, including the DNA damage response (DDR) pathway. Constitutive activation of DDR proteins has been observed in human tumor specimens from different cancer stages, including precancerous and metastatic cancers, although not in normal tissues. The tumor-suppressive role of DDR activity during the premalignant stage has been studied, and strong evidence is emerging for an oncogenic role for DDR proteins such as DNA-PK and CHK1 during the later stages of tumor development. However, the majority of current cancer therapies induce DNA damage, potentially exacerbating protumorigenic genomic instability and enabling the development of resistance. Therefore, elucidating the molecular basis of DNA damagemediated genomic instability and its role in tumorigenesis is critical. Finally, I discuss the potential existence of distinct DNA damage thresholds at various stages of tumorigenesis and what the ramifications of such thresholds would be, including the ambiguous role of the DDR pathway in human cancers, therapyinduced malignancies, and enhanced therapies.

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Section: Emerging Evidence For the Role Of Constitutive Dna Damage Inmentioning

confidence: 99%

DNA Damage in Cancer Therapeutics: A Boon or a Curse?

2015

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“…It was reported recently that DNA damage caused by ionizing radiation leads to the activation of AR, which in turn induces the expression of DNA repair genes that promote the survival of irradiated prostate cancer cells (47,48). Based on these reports, we expected that AR-inactivation would down regulate DDR signaling pathways and block the repair of damaged telomeres.…”

Section: Discussionmentioning

confidence: 94%

ATM Inhibition Potentiates Death of Androgen Receptor-inactivated Prostate Cancer Cells with Telomere Dysfunction

Reddy

Ciavattone

et al. 2015

Journal of Biological Chemistry

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Background: Androgen receptor (AR) inactivation causes telomere dysfunction. Results: AR-inactivation-induced telomere dysfunction led to the activation of ATM at telomeres, and ATM inhibition blocked repair of damaged telomeric DNA and augmented cell death. Conclusion: ATM promotes survival of AR-inactivated prostate cancer cells with telomere dysfunction. Significance: ATM inhibitors may potentiate the efficacy of AR-targeted therapies for the treatment of prostate cancer.

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“…In this first-in-human proof-ofmechanism study, Tarish and colleagues demonstrated longitudinally that castration primarily affected both Ku and DNAPKcs expression in response to radiotherapy, leading to significant impairment of the nonhomologous end-joining (NHEJ) pathway of DSB (5). In parallel, Polkinghorn and colleagues and Goodwin and colleagues also observed a radiosensitization effect as a consequence of androgen blockade, and attributed this to the transcriptional downregulation of DNA repairrelated genes, with DNA-PKcs being a key target (6,7).…”

Section: 2mentioning

confidence: 93%

Testosterone in Androgen Receptor Signaling and DNA Repair: Enemy or Frenemy?

Chua

Bristow

2016

Clinical Cancer Research

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Androgen suppression mediates transcriptional downregulation of DNA repair genes. Stimulation with supraphysiologic levels of dihydrotestosterone induces formation of lethal DNA breaks through recruitment of topoisomerase II enzymes to fragile DNA sites. Bipolar castration and stimulation that contributes to increasing DNA damage represents a novel strategy of sensitizing prostate cancer to cytotoxic therapies, including radiotherapy. Clin Cancer Res; 22(13); 3124-6. Ó2016 AACR.See related article by Hedayati et al., p. 3310 In this issue of Clinical Cancer Research, Hedayati and colleagues (1) report a novel, but possibly counterintuitive, strategy of exploiting sequential androgen suppression and stimulation to increasingly sensitize prostate cancer cells to radiotherapy. They attributed this effect to the induction of transient DNA doublestrand breaks (DSB) following a combination of androgen deprivation and supraphysiologic levels of dihydrotestosterone. This DNA damage response occurs through an exclusive interaction between the androgen receptor (AR) and topoisomerase II beta (TOP2B). This increased accumulation of DSB following irradiation was significant enough to inhibit tumor growth in vivo.The combination of androgen suppression and radiotherapy is a time-honored treatment regime with proven efficacy of advancing cure rates in patients with high-risk and locally advanced prostate cancer. Numerous randomized trials, testing a variety of castration approaches, have conclusively confirmed the synergism between androgen suppression and radiation, reporting better tumor control rates (pooled HR 1.67) and reduction of distant metastases (pooled HR 1.63) when compared with radiotherapy alone (2). On the basis of the documented effects on both local and systemic disease, it is widely perceived that combined modality therapy with suppression of the AR axis simultaneously enhances the cytotoxic effects of radiotherapy on the primary prostate cancer and also targets occult metastases.The mechanistic basis of this clinical observation is starting to mature as increasing evidence indicates that activation of the AR axis exerts an influence on the cellular DNA repair machinery and overall DNA damage response (Fig. 1). In response to genotoxic stress, androgen ligand binding to the AR triggers a cascade of signaling events that promotes the assembly of transcriptional elements leading to the overexpression of DNA repair genes involved in DNA damage sensing, DSB repair, base excision repair (BER), and mismatch repair (MMR; ref.3). The process of ARdependent transcriptional regulation is further modulated by the receptor binding with repair proteins, such as Ku, DNA-dependent protein kinase (catalytic subunit; DNA-PKcs), and PARP1; these proteins also function as AR coactivators (4).Given the positive-feedback circuit linking AR axis stimulation and DNA repair, it would suggest, in principle, that targeting the AR axis represents a very sound and attractive strategy for potentiating the DNA-damaging effects of cyto...

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A Hormone–DNA Repair Circuit Governs the Response to Genotoxic Insult

Cited by 306 publications

References 73 publications

DNA Damage in Cancer Therapeutics: A Boon or a Curse?

DNA Damage in Cancer Therapeutics: A Boon or a Curse?

ATM Inhibition Potentiates Death of Androgen Receptor-inactivated Prostate Cancer Cells with Telomere Dysfunction

Testosterone in Androgen Receptor Signaling and DNA Repair: Enemy or Frenemy?

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