Oxidative DNA Damage in Radiation Therapy Related Early Adverse Skin Reactions in Breast Cancer

DNA damage and base excision repair (BER) are actively involved in the modulation of DNA methylation and demethylation. However, the underlying molecular mechanisms remain unclear. In this study, we seek to understand the mechanisms by exploring the effects of oxidative DNA damage on the DNA methylation pattern of the tumor suppressor breast cancer 1 (BRCA1) gene in the human embryonic kidney (HEK) HEK293H cells. We found that oxidative DNA damage simultaneously induced DNA demethylation and generation of new methylation sites at the CpGs located at the promoter and transcribed regions of the gene ranging from −189 to +27 in human cells. We demonstrated that DNA damage-induced demethylation was mediated by nucleotide misincorporation by DNA polymerase β (pol β). Surprisingly, we found that the generation of new DNA methylation sites was mediated by coordination between pol β and the de novo DNA methyltransferase, DNA methyltransferase 3b (DNMT3b), through the interaction between the two enzymes in the promoter and encoding regions of the BRCA1 gene. Our study provides the first evidence that oxidative DNA damage can cause dynamic changes in DNA methylation in the BRCA1 gene through the crosstalk between BER and de novo DNA methylation.

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Correction: Huang, H.W.; et al. Sinularin Selectively Kills Breast Cancer Cells Showing G2/M Arrest, Apoptosis, and Oxidative DNA Damage. Molecules 2018, 23, 849

Molecules ◽

10.3390/molecules23071670 ◽

2018 ◽

Vol 23 (7) ◽

pp. 1670

Author(s):

Hurng-Wern Huang ◽

Jen-Yang Tang ◽

Fu Ou-Yang ◽

Hui-Ru Wang ◽

Pei-Ying Guan ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Oxidative Dna Damage

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Induction of NAD(P)H-quinone oxidoreductase 1 by antioxidants in female ACI rats is associated with decrease in oxidative DNA damage and inhibition of estrogen-induced breast cancer

Carcinogenesis ◽

10.1093/carcin/bgr237 ◽

2011 ◽

Vol 33 (1) ◽

pp. 156-163 ◽

Cited By ~ 33

Author(s):

B. Singh ◽

N. K. Bhat ◽

H. K. Bhat

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Oxidative Dna Damage ◽

Quinone Oxidoreductase

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Five day accelerated partial breast irradiation (APBI) using stereotactic body radiation therapy (SBRT) in stage 0-II breast cancer: A report of 135 cases with up to two-year follow-up.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e12596 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e12596-e12596

Author(s):

Rufus J. Mark ◽

Valerie Gorman ◽

Steven McCullough

Keyword(s):

Breast Cancer ◽

Radiation Therapy ◽

Target Volume ◽

Accelerated Partial Breast Irradiation ◽

Partial Breast Irradiation ◽

Skin Reactions ◽

Cosmetic Results ◽

Non Invasive ◽

External Radiation Therapy

e12596 Background: Randomized trials in stage 0-II breast cancer have proven that APBI given via HDR implant in 5 days is equivalent to whole breast External Radiation Therapy (XRT) given in 5-6 weeks in regard to breast tumor local recurrence (LR). However, complications have been significant. Recently APBI using non-invasive IMRT given in 5 fractions has been shown in another randomized trial to be equivalent to XRT in 6 weeks, with respect to LR. IMRT was superior in regard to acute effects, late effects, and cosmesis. In the randomized clinical trial of APBI IMRT, the Clinical Target Volume (CTV) was defined by the injection of individual fiducial markers bordering the surgical cavity. At our institution, we have used the Biozorb fiducial system to localize the CTV for IMRT. We sought to confirm the APBI IMRT results with this simpler less labor intensive fiducial placement system. Methods: Between 2017 and 2020, 135 patients have undergone SBRT targeted to a Biozorb defined CTV with the walls of the surgical cavity sewn to the Biozorb device. Eligible patients were older than age 40, had tumor sizes < 3 cm, negative surgical margins, and negative sentinel node dissections. SBRT dose was 30 Gy given in 5 fractions. Dose Constraints were as follows: V-30 Gy < 105%, Ipsilateral Breast V-15 Gy < 50%, Ipsilateral Lung V-10 Gy < 20%, Contralateral Lung V-5 Gy < 10%, Heart V-3 Gy < 20%, Contralateral Breast Dmax < 2 Gy and Skin Dmax < 27 Gy. The Planning Target Volume (PTV) ranged from 27 to 355 cc with a median of 80 cc. PTV = CTV + 1-2 cm. Results: Follow-up ranged from 1-26 months with a median of 12 months. LR has been 0% (0/135). There have been no skin reactions or seromas. Infection has occurred in one patient (0.7%). Three (2.2%) patients developed pain around the Biozorb site. This resolved within 2 days on a short course of steroids in all cases. Cosmetic results as rated by the Surgeon, Radiation Oncologist, and Nurse, were rated excellent in 98.5% (133/135) of cases. Conclusions: Non-invasive APBI with SBRT given qd over 5 days targeted to Biozorb has resulted in LR, complications, and cosmetic results which compare favorably to invasive APBI given bid with HDR implant. At last follow-up, there have been no LR, skin reactions, or significant complications. Cosmesis has been excellent in 98.5% of patients.

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