Low p53 Binding Protein 1 (53BP1) Expression Is Associated With Increased Local Recurrence in Breast Cancer Patients Treated With Breast-Conserving Surgery and Radiotherapy

Neboori, Hanmanth J.; Haffty, Bruce G.; Wu, Hao; Yang, Qifeng; Aly, Amal; Goyal, Sharad; Schiff, Devora; Moran, Meena S.; Golhar, Ryan; Chen, Chunxia; Moore, Dirk F.; Ganesan, Shridar

doi:10.1016/j.ijrobp.2012.01.089

Cited by 29 publications

(30 citation statements)

References 23 publications

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“…We also report on 53BP1 status as independent predictive biomarker in the whole cohort as this analysis has not been described elsewhere. Furthermore, we investigated independent value of 53BP1 in the triple-negative (TN) subgroup because aberrant expression has been reported to be enriched in this subgroup of patients (13,(31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

High XIST and Low 53BP1 Expression Predict Poor Outcome after High-Dose Alkylating Chemotherapy in Patients with a BRCA1-like Breast Cancer

Schouten

Vollebergh

Opdam

et al. 2016

Molecular Cancer Therapeutics

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In previous studies, high expression of XIST and low expression of 53BP1 were respectively associated with poor systemic therapy outcome in patients and therapy resistance in BRCA1-deficient mouse tumor models, but have not been evaluated in BRCA1-deficient patients. Previously, we demonstrated that classifying breast cancer copy number profiles as BRCA1-like or non-BRCA1-like identified patients enriched for defects in BRCA1 that benefit from high-dose (HD) alkylating chemotherapy compared with a conventional standard regimen. We investigated whether XIST and 53BP1 expression predicted poor outcome of HD chemotherapy within 28 BRCA1-like patients from a trial randomizing between HD [4 cycles 5-fluorouracil, epirubicin, cyclophosphamide (FEC) followed by 1 cycle HD carboplatin, thiotepa, cyclophosphamide] or conventional chemotherapy (5 cycles FEC), for which both XIST and 53BP1 statuses were available. High RNA expression of XIST (n ¼ 5) and low protein expression of 53BP1 (n ¼ 3) expression did not coincide. Patients with either one had poor outcome after treatment with HD chemotherapy, whereas patients with low expression of XIST and high expression of 53BP1 derived substantial benefit of this regimen on recurrence-free survival, disease-free survival, and overall survival, corroborating preclinical findings. XIST and 53BP1 may be predictive biomarkers in BRCA1-like breast cancer. Mol Cancer Ther; 15(1); 190-8. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

High XIST and Low 53BP1 Expression Predict Poor Outcome after High-Dose Alkylating Chemotherapy in Patients with a BRCA1-like Breast Cancer

Schouten

Vollebergh

Opdam

et al. 2016

Molecular Cancer Therapeutics

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“…Loss of 53BP1 has been identified in a variety of tumors (101), particularly those with BRCA mutation (102). Studies have suggested that loss of 53BP1 is able to reverse many aspects of the phenotype associated with BRCA1 loss (102–104), including restoring HR ability and resistance to PARP inhibitors and RT (102,103,105). RT resistance was observed in breast cancer patients with low 53BP1 expression (105) despite the hypersensitivity to IR in cells with 53BP1 deficiency in numerous different cancer cell lines and animal models (106–108).…”

Section: The Potential Factors Contributing To Inconsistencesmentioning

confidence: 99%

BRCA1 Mutation: A Predictive Marker for Radiation Therapy?

Kan

Zhang

2015

International Journal of Radiation Oncology*Biology*Physics

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DNA repair, particularly DNA double strand breaks (DSBs) repair, is essential for the survival of both normal and cancer cells. An elaborate repair mechanism has been developed in cells in order to efficiently repair the damaged DNA. The pathways that are predominately involved in DSBs repair are homologous recombination (HR) and classical nonhomologous end-joining (cNHEJ) although alternative NHEJ (aNHEJ), a third DSBs repair pathway, may also be important in certain contexts. The protein of BRCA1 encoded by the tumor suppressor gene BRCA1 regulates all DSBs repair pathways. Given the fact that DSBs represent the most biologically significant lesions induced by ionizing radiation (IR) and impaired DSBs repair leads to radiation sensitivity it has been expected that cancer patients with BRCA1 mutations should benefit from radiation therapy (RT). However, the clinical data are conflicting and inconclusive. Here, we provide an overview about the current status of the data regarding BRCA1 deficiency and RT sensitivity in both experimental models and clinical investigations. In addition, we will discuss a strategy to potentiate the effects of RT by poly(ADP ribose) polymerase (PARP) inhibitors, the pharmacologic drugs that are being investigated as a monotherapy for the treatment of patients with BRCA 1/2 mutations.

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“…Low expression level of 53BP1 was found to be associated with poor clinical outcome in triple negative breast cancer patients with BRCA1 mutation (12,15), as well as resistance to genotoxins and poly(ADP-ribose) polymerase inhibitors (12,16,17). This finding is probably because loss of 53BP1 restored HR and promoted cell survival (12)(13)(14).…”

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confidence: 96%

UbcH7 regulates 53BP1 stability and DSB repair

Han¹,

Zhang²,

Chung³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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DNA double-strand break (DSB) repair is not only key to genome stability but is also an important anticancer target. Through an shRNA library-based screening, we identified ubiquitin-conjugating enzyme H7 (UbcH7, also known as Ube2L3), a ubiquitin E2 enzyme, as a critical player in DSB repair. UbcH7 regulates both the steady-state and replicative stress-induced ubiquitination and proteasome-dependent degradation of the tumor suppressor p53-binding protein 1 (53BP1). Phosphorylation of 53BP1 at the N terminus is involved in the replicative stress-induced 53BP1 degradation. Depletion of UbcH7 stabilizes 53BP1, leading to inhibition of DSB end resection. Therefore, UbcH7-depleted cells display increased nonhomologous end-joining and reduced homologous recombination for DSB repair. Accordingly, UbcH7-depleted cells are sensitive to DNA damage likely because they mainly used the errorprone nonhomologous end-joining pathway to repair DSBs. Our studies reveal a novel layer of regulation of the DSB repair choice and propose an innovative approach to enhance the effect of radiotherapy or chemotherapy through stabilizing 53BP1.DNA damage response | UbcH7 | 53BP1 | protein degradation | DSB repair P rompt response to double-strand breaks (DSBs) caused by, for example, ionization radiation (IR), requires sequential and coordinated assembly of DNA damage response (DDR) proteins at damage sites (1). Recent research findings reveal key roles of the tumor suppressor p53-binding protein 1 (53BP1) and BRCA1 in the decision making of DSB repair. 53BP1, together with Rif1, suppress BRCA1-dependent homologous recombination (HR), thereby promoting nonhomologous end-joining (NHEJ) in G1 phase (2-6). Conversely, BRCA1 antagonizes 53BP1/Rif1, favoring HR in S and G2 phases (7,8). In the absence of BRCA1 or with enhanced retention of 53BP1 at DSB sites, cells primarily use the error-prone NHEJ to repair DSBs throughout the cell cycle, which leads to gene rearrangement, cell death, and increased sensitivity to anticancer therapies (9-11). Consistently, BRCA1-null mice are early embryonic lethal (12, 13) and codepletion of TP53BP1 rescued the lethality phenotype of BRCA1-null mice (12)(13)(14).Low expression level of 53BP1 was found to be associated with poor clinical outcome in triple negative breast cancer patients with BRCA1 mutation (12, 15), as well as resistance to genotoxins and poly(ADP-ribose) polymerase inhibitors (12,16,17). This finding is probably because loss of 53BP1 restored HR and promoted cell survival (12-14). Reduced expression of 53BP1 was also observed in tumors from the brain (18), lymph node (19), and pancreas (20). These data indicate that loss of 53BP1 might be a common mechanism for advanced tumors to evade from radiotherapy or chemotherapy. However, molecular mechanisms controlling the protein level of 53BP1 remain less well understood.Here we show that UbcH7, an E2 enzyme involved in the ubiquitin (Ub) pathway, controls the protein stability of 53BP1, thereby determining the DSB repair choice. Loss of UbcH7 sta...

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Low p53 Binding Protein 1 (53BP1) Expression Is Associated With Increased Local Recurrence in Breast Cancer Patients Treated With Breast-Conserving Surgery and Radiotherapy

Cited by 29 publications

References 23 publications

High XIST and Low 53BP1 Expression Predict Poor Outcome after High-Dose Alkylating Chemotherapy in Patients with a BRCA1-like Breast Cancer

High XIST and Low 53BP1 Expression Predict Poor Outcome after High-Dose Alkylating Chemotherapy in Patients with a BRCA1-like Breast Cancer

BRCA1 Mutation: A Predictive Marker for Radiation Therapy?

UbcH7 regulates 53BP1 stability and DSB repair

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