BRCA1 Mutation: A Predictive Marker for Radiation Therapy?

Kan, Charlene E.; Zhang, Junran

doi:10.1016/j.ijrobp.2015.05.037

Cited by 46 publications

(33 citation statements)

References 130 publications

(164 reference statements)

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“…BRCA1 is one of the key regulators of DNA repair, and loss of BRCA1 expression results in radiosensitization in cells and animal preclinical models . To analyze the role of BRCA1 in PCa cell radiosensitivity, we used radiobiological colony formation analysis.…”

Section: Resultsmentioning

confidence: 99%

BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

Gorodetska

Lukiyanchuk

Peitzsch

et al. 2019

Intl Journal of Cancer

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Prostate cancer (PCa) is the second most common malignancy and the sixth leading cause of cancer-related death among men worldwide. Prostate carcinogenesis is driven by the accumulation of genetic and epigenetic aberrations, which regulate cancer cell transition between a stem-and nonstem-cell state and accelerate tumor evolution. Elevated expression of enhancer of zeste homolog 2 (EZH2) histone methyltransferase, a core member of the polycomb repressive complex 2 (PRC2), results in cancer progression through histone methylation-driven tumor cells dedifferentiation. Previous studies demonstrated that tumor suppressor breast cancer 1 (BRCA1) is a negative regulator of PRC2-dependent H3K27 methylation. Our recent studies revealed that inhibition of EZH2-mediated histone methylation radiosensitizes prostate cancer stem cells (CSCs) population. However, the link between BRCA1 and EZH2 in regulation of prostate CSCs remains elusive. Present study demonstrated that BRCA1 and EZH2 are coregulated in patients' tumors and PCa cell lines, and cooperate in regulation of CSC phenotype and properties. Knockdown of BRCA1 expression significantly increases the number and the size of tumor spheres. Inhibition of BRCA1 and EZH2 expression leads to an increase of aldehyde dehydrogenase (ALDH)-positive cell population that is, at least partially, attributed to the upregulation of ALDH1A3 protein. Treatment with a global histone methylation inhibitor 3-Deazaneplanocin A abrogates this regulation, downregulates BRCA1 and EZH2 expression and has an inhibitory effect on the tumorigenic properties of radioresistant PCa cells in vivo. We found that EZH2/BRCA1 signaling mechanisms play an important role in the maintenance of prostate CSC properties and may be a promising target for tumor treatment.

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Section: Resultsmentioning

confidence: 99%

BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

Gorodetska

Lukiyanchuk

Peitzsch

et al. 2019

Intl Journal of Cancer

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“…The impaired ability for DSB repair due to BRCA1 mutations contributes to radiation sensitivity. Interestingly, BRCA1 expression restores radiation resistance in BRCA1-defective cancer cells through enhancement of transcriptioncoupled DNA repair [31]. Future trials may combine PARP inhibitors with RT to synergize with PARP inhibitors or to overcome resistance.…”

Section: Parp Inhibitorsmentioning

confidence: 99%

Germline and Somatic Mutations in Prostate Cancer: Focus on Defective DNA Repair, PARP Inhibitors and Immunotherapy

et al. 2020

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“…Cells and animal models have demonstrated that defective breast cancer gene 1/2 ( BRCA1/2) which encodes the repair system for DNA DSB is involved in radiation resistance. Clinical trials showed that breast cancers with BRCA1 (-/-) exhibit elevated sensitivity to radiation therapy [ 44 ].…”

Section: Improving Tumor Elimination By Targeting Known Radiation Senmentioning

confidence: 99%

Improving radiotherapy in cancer treatment: Promises and challenges

2017

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Effective radiotherapy for cancer has relied on the promise of maximally eradicating tumor cells while minimally killing normal cells. Technological advancement has provided state-of-the-art instrumentation that enables delivery of radiotherapy with great precision to tumor lesions with substantial reduced injury to normal tissues. Moreover, better understanding of radiobiology, particularly the mechanisms of radiation sensitivity and resistance in tumor lesions and toxicity in normal tissues, has improved the treatment efficacy of radiotherapy. Previous mechanism-based studies have identified many cellular targets that can affect radiation sensitivity, notably reactive oxygen species, DNA-damaging response signals, and tumor microenvironments. Several radiation sensitizers and protectors have been developed and clinically evaluated; however, many of these results are inconclusive, indicating that improvement remains needed. In this era of personalized medicine in which patients’ genetic variations, transcriptome and proteomics, tumor metabolism and microenvironment, and tumor immunity are available. These new developments have provided opportunity for new target discovery. Several radiotherapy sensitivity-associated “gene signatures” have been reported although clinical validations are needed. Recently, several immune modifiers have been shown to associate with improved radiotherapy in preclinical models and in early clinical trials. Combination of radiotherapy and immunocheckpoint blockade has shown promising results especially in targeting metastatic tumors through abscopal response. In this article, we succinctly review recent advancements in the areas of mechanism-driven targets and exploitation of new targets from current radio-oncogenomic and radiation-immunotherapeutic approaches that bear clinical implications for improving the treatment efficacy of radiotherapy.

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BRCA1 Mutation: A Predictive Marker for Radiation Therapy?

Cited by 46 publications

References 130 publications

BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

Germline and Somatic Mutations in Prostate Cancer: Focus on Defective DNA Repair, PARP Inhibitors and Immunotherapy

Improving radiotherapy in cancer treatment: Promises and challenges

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