The predictive value of 53BP1 and BRCA1 mRNA expression in advanced non-small-cell lung cancer patients treated with first-line platinum-based chemotherapy

Bonanno, Laura; Costa, Carlota; Majem, Margarita; Sánchez, José Javier; Giménez‐Capitán, Ana; Rodríguez, I.; Vergnenègre, A.; Massutí, Bartomeu; Favaretto, Adolfo; Pallarès, Cinta; Tarón, Miquel; Rosell, Rafael

doi:10.18632/oncotarget.1157

Cited by 22 publications

(10 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other way, inhibiting VRK1 role in DNA damage response to ionizing radiation or chemotherapy [21] can make tumor cells more sensitive to these treatments, and might consequently permit a reduction of toxic doses in new protocols based on combination therapies, once VRK1 inhibitors become available in the future. This role of VRK1 in DNA-damage response is in agreement with the predictive role of 53BP1 and BRCA1 expression in breast cancer [44, 45]. …”

Section: Resultssupporting

confidence: 78%

Vaccinia-related kinase 1 (VRK1) confers resistance to DNA-damaging agents in human breast cancer by affecting DNA damage response

et al. 2014

View full text Add to dashboard Cite

Vaccinia-related kinase 1 (VRK1) belongs to a group of sixteen kinases associated to a poorer prognosis in human breast carcinomas, particularly in estrogen receptor positive cases based on gene expression arrays. In this work we have studied the potential molecular mechanism by which the VRK1 protein can contribute to a poorer prognosis in this disease. For this aim it was first analyzed by immunohistochemistry the VRK1 protein level in normal breast and in one hundred and thirty six cases of human breast cancer. The effect of VRK1 to protect against DNA damage was determined by studying the effect of its knockdown on the formation of DNA repair foci assembled on 53BP1 in response to treatment with ionizing radiation or doxorubicin in two breast cancer cell lines. VRK1 protein was detected in normal breast and in breast carcinomas at high levels in ER and PR positive tumors. VRK1 protein level was significantly lower in ERBB2 positive cases. Next, to identify a mechanism that can link VRK1 to poorer prognosis, VRK1 was knocked-down in two breast cancer cell lines that were treated with ionizing radiation or doxorubicin, both inducing DNA damage. Loss of VRK1 resulted in reduced formation of DNA-damage repair foci complexes assembled on the 53BP1 scaffold protein, and this effect was independent of damaging agent or cell type. This observation is consistent with detection of high VRK1 protein levels in ER and PR positive breast cancers. We conclude that VRK1 can contribute to make these tumors more resistant to DNA damage-based therapies, such as ionizing radiation or doxorubicin, which is consistent with its association to a poor prognosis in ER positive breast cancer. VRK1 is potential target kinase for development of new specific inhibitors which can facilitate sensitization to other treatments in combination therapies; or alternatively be used as a new cancer drugs.

show abstract

Section: Resultssupporting

confidence: 78%

Vaccinia-related kinase 1 (VRK1) confers resistance to DNA-damaging agents in human breast cancer by affecting DNA damage response

et al. 2014

View full text Add to dashboard Cite

show abstract

“…BRCA1 is a tumor suppressor gene located on chromosome 17q21 that has been intensively investigated as participating in the repair of cisplatin-induced DNA double-strand breaks [ 42 ]. Accordingly, a decrease in BRCA1 expression leads to a decreased proficiency in DNA repair, increased cisplatin sensitivity and improved survival in non-small cell lung cancer [ 43 , 44 ], breast cancer [ 45 ], advanced esophageal squamous cell carcinoma [ 46 ] and ovarian cancer [ 47 ] patients. However, it is currently unknown whether BRCA1 expression correlates with cisplatin sensitivity in TSCC.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial fission determines cisplatin sensitivity in tongue squamous cell carcinoma through the BRCA1-miR-593-5p–MFF axis

et al. 2015

View full text Add to dashboard Cite

Cisplatin has been widely employed as a cornerstone chemotherapy treatment for a wide spectrum of solid neoplasms; increasing tumor responsiveness to cisplatin has been a topic of interest for the past 30 years. Strong evidence has indicated that mitochondrial fission participates in the regulation of apoptosis in many diseases; however, whether mitochondrial fission regulates cisplatin sensitivity remains poorly understood. Here, we show that MFF mediated mitochondrial fission and apoptosis in tongue squamous cell carcinoma (TSCC) cells after cisplatin treatment and that miR-593-5p was downregulated in this process. miR-593-5p attenuated mitochondrial fission and cisplatin sensitivity by targeting the 3′ untranslated region sequence of MFF and inhibiting its translation. In exploring the underlying mechanism of miR-593-5p downregulation, we observed that BRCA1 transactivated miR-593-5p expression and attenuated cisplatin sensitivity in vitro. The BRCA1-miR-593-5p-MFF axis also affected cisplatin sensitivity in vivo. Importantly, in a retrospective analysis of multiple centers, we further found that the BRCA1-miR-593-5p-MFF axis was significantly associated with cisplatin sensitivity and the survival of patients with TSCC. Together, our data reveal a model for mitochondrial fission regulation at the transcriptional and post-transcriptional levels; we also reveal a new pathway for BRCA1 in determining cisplatin sensitivity through the mitochondrial fission program.

show abstract

“…To determine whether the increased genomic instability associated with Brca1 S971A/S971A mice results from a deficiency in the HR pathway, primary mouse embryonic fibroblasts (MEFs) carrying either Brca1 C/C or Brca1 S971A/S971A were treated with a poly(ADP-ribose) polymerase (PARP) inhibitor (KU-0058948) and their survival was examined in a clonogenic assay. [29][30][31][32] Two pairs of MEFs from independent breedings of mice were used: the A2/A7 pair (p53 ¡/¡ background, breeding between Brca1 S971A/C p53 ¡/¡ mice) and the B8/B9 pair (p53 C/¡ background, breeding between Brca1 S971A/C p53 C/C and Brca1 S971A/C p53 ¡/¡ mice). In a p53 ¡/¡ background, Brca1 S971A/S971A MEFs displayed moderate, but statistically significant, sensitivity to the PARP inhibitor as compared to Brca1 C/C MEFs (Fig.…”

Section: Abrogation Of Chk2 Phosphorylation On Mouse Brca1 Confers Pamentioning

confidence: 99%

Damage-induced BRCA1 phosphorylation by Chk2 contributes to the timing of end resection

Parameswaran

Chiang

et al. 2015

Cell Cycle

View full text Add to dashboard Cite

The BRCA1 tumor suppressor plays an important role in homologous recombination (HR)-mediated DNA double-strand-break (DSB) repair. BRCA1 is phosphorylated by Chk2 kinase upon γ-irradiation, but the role of Chk2 phosphorylation is not understood. Here, we report that abrogation of Chk2 phosphorylation on BRCA1 delays end resection and the dispersion of BRCA1 from DSBs but does not affect the assembly of Mre11/Rad50/NBS1 (MRN) and CtIP at DSBs. Moreover, we show that BRCA1 is ubiquitinated by SCF(Skp2) and that abrogation of Chk2 phosphorylation impairs its ubiquitination. Our study suggests that BRCA1 is more than a scaffold protein to assemble HR repair proteins at DSBs, but that Chk2 phosphorylation of BRCA1 also serves as a built-in clock for HR repair of DSBs. BRCA1 is known to inhibit Mre11 nuclease activity. SCF(Skp2) activity appears at late G1 and peaks at S/G2, and is known to ubiquitinate phosphodegron motifs. The removal of BRCA1 from DSBs by SCF(Skp2)-mediated degradation terminates BRCA1-mediated inhibition of Mre11 nuclease activity, allowing for end resection and restricting the initiation of HR to the S/G2 phases of the cell cycle.

show abstract

The predictive value of 53BP1 and BRCA1 mRNA expression in advanced non-small-cell lung cancer patients treated with first-line platinum-based chemotherapy

Cited by 22 publications

References 38 publications

Vaccinia-related kinase 1 (VRK1) confers resistance to DNA-damaging agents in human breast cancer by affecting DNA damage response

Vaccinia-related kinase 1 (VRK1) confers resistance to DNA-damaging agents in human breast cancer by affecting DNA damage response

Mitochondrial fission determines cisplatin sensitivity in tongue squamous cell carcinoma through the BRCA1-miR-593-5p–MFF axis

Damage-induced BRCA1 phosphorylation by Chk2 contributes to the timing of end resection

Contact Info

Product

Resources

About