Lack of functional pRb results in attenuated recovery of mRNA synthesis and increased apoptosis following UV radiation in human breast cancer cells

Billecke, Christine; Ljungman, Mats; McKay, Bruce C.; Rehemtulla, Alnawaz; Taneja, Neelam; Ethier, Stephen P.

doi:10.1038/sj.onc.1205546

Cited by 27 publications

(17 citation statements)

References 40 publications

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“…These results are supported by previous findings showing that transfection of cells with the HPV16 E6 gene sensitizes cells to genotoxic stress [15]. E6 expression impairs nucleotide excision repair, reducing the cells' capability to recover from DNA damage [14], and E7 expression reduces survival after UV irradiation [16]. Impairment of cell-cycle control due to Rb and p53 down-regulation would be expected to result in cell death in response to environmental stress.…”

Section: Discussionsupporting

confidence: 85%

Loss of Robustness and Addiction to IGF1 during Early Keratinocyte Transformation by Human Papilloma Virus 16

Geiger

Levitzki

2007

PLoS ONE

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Infection of keratinocytes with high risk human Papilloma virus causes immortalization, and when followed by further mutations, leads to cervical cancer and other anogenital tumors. Here we monitor the progressive loss of robustness in an in vitro model of the early stages of transformation that comprises normal keratinocytes and progressive passages of HPV16 immortalized cells. As transformation progresses, the cells acquire higher proliferation rates and gain the ability to grow in soft agar. Concurrently, the cells lose robustness, becoming more sensitive to serum starvation and DNA damage by Cisplatin. Loss of robustness in the course of transformation correlates with significant reductions in the activities of the anti-apoptotic proteins PKB/Akt, Erk, Jnk and p38 both under normal growth conditions and upon stress. In parallel, loss of robustness is manifested by the shrinkage of the number of growth factors that can rescue starving cells from apoptosis, with the emergence of dependence solely on IGF1. Treatment with IGF1 activates PKB/Akt and Jnk and through them inhibits p53, rescuing the cells from starvation. We conclude that transformation in this model induces higher susceptibility of cells to stress due to reduced anti-apoptotic signaling and hyper-activation of p53 upon stress.

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Section: Discussionsupporting

confidence: 85%

Loss of Robustness and Addiction to IGF1 during Early Keratinocyte Transformation by Human Papilloma Virus 16

Geiger

Levitzki

2007

PLoS ONE

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“…Treatment with TRAIL alone in MDA468 cells will induce apoptosis (Figure 8a), however, this cell line is resistant to both TNF-a and FasL-induced apoptosis (data not shown), consistent with studies that show MDA468 cells deficient in Fas (Keane et al, 1996) and unresponsive to FasL or Fas receptor agonists (Billecke et al, 2002). Nevertheless, after confirming the ability of neutralizing antibody to DR4 and DR5 to block completely the apoptotic effect of TRAIL (Figure 8a), and confirming that IRF-1 does not induce TRAIL (data not shown), we then used the highest recommended doses of neutralizing antibody for each death ligand/receptor to confirm that secretion of TNF, TRAIL and FasL are not involved in IRF-1-induced apoptosis in MDA468 cells (Figure 8b).…”

Section: Screening For Individual Caspases Involved In Irf-1-induced supporting

confidence: 88%

Interferon regulatory factor-1-induced apoptosis mediated by a ligand-independent fas-associated death domain pathway in breast cancer cells

et al. 2007

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Interferon (IFN) regulatory factor-1 (IRF-1) is a transcription factor that has apoptotic anti-tumor activity. In breast cancer cell types, IRF-1 is implicated in mediating apoptosis by both novel and established anti-tumor agents, including the anti-estrogens tamoxifen and faslodex. Here we demonstrate that in MDA468 breast cancer cells, apoptosis by IFN-c is mediated by IRF-1 and IFN-c, and IRF-1-induced apoptosis is caspase-mediated. IRF-1 induction results in cleavage of caspase-8, -3 and -7, and application of caspase inhibitors attenuate activated cleavage products. IRF-1-induced apoptosis involves caspase-8 since apoptosis is significantly decreased by the caspase-8-specific inhibitor IETD, c-FLIP expression and in caspase-8-deficient cancer cells. Furthermore, we demonstrate that IRF-1-induced apoptosis requires fas-associated death domain (FADD) since dominant-negative FADD expressing cells resist IRF-1-induced apoptosis and activated downstream products. Immunofluorescent studies demonstrate perinuclear colocalization of FADD and caspase-8. Despite the known role of FADD in mediating death-ligand induced apoptosis, neutralizing antibodies against classical death receptors do not inhibit IRF-1 induced apoptosis, and no secreted ligand appears to be involved since MDA468 coincubated with IRF-1 transfected cells do not apoptose. Therefore, we demonstrate that IRF-1 induces a ligand-independent FADD/caspase-8-mediated apoptosis in breast cancer cells.

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“…One of the main reasons probably is its high expression of EGFR receptors (almost ten times higher) compared to other TNBC cells lines, potentially delivering significantly higher alpha doses to the tumor cells. In addition, the cell survival curve with gamma-rays showed that the MDA-MB-468 cells are sensitive to radiation and exhibit a diminished shoulder region, consistent with its radiosensitivity to UV radiation attributed to the deficient RB gene and deficiency in recovery of mRNA synthesis (52). The possible dis-regulation of DSB repair in MDA-MB-468 cells remains to be studied.…”

Section: Discussionmentioning

confidence: 80%

Targeting Aberrant DNA Double-Strand Break Repair in Triple-Negative Breast Cancer with Alpha-Particle Emitter Radiolabeled Anti-EGFR Antibody

Song

Hedayati²,

Hobbs

et al. 2013

Molecular Cancer Therapeutics

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The higher potential efficacy of alpha-particle radiopharmaceutical therapy lies in the 3 to 8-fold greater biological effectiveness (RBE) of alpha particles relative to photon or beta-particle radiation. This greater RBE, however, also applies to normal tissue, thereby reducing the potential advantage of high RBE. Since alpha particles typically cause DNA double strand breaks (DSBs), targeting tumors that are defective in DSB repair effectively increases the RBE, yielding a secondary, RBE-based differentiation between tumor and normal tissue that is complementary to conventional, receptor-mediated tumor targeting. In some triple negative breast cancers (TNBC, ER−/PR−/HER-2−), germline mutation in BRCA-1, a key gene in homologous recombination (HR) DSB repair, predisposes patients to early onset of breast cancer. These patients have few treatment options once the cancer has metastasized. In this study, we investigated the efficacy of alpha particle emitter, 213Bi labeled anti-EGFR antibody, Cetuximab, in BRCA-1 defective TNBC. 213Bi-Cetuximab was found to be significantly more effective in the BRCA-1 mutated TNBC cell line HCC1937 than BRCA-1 competent TNBC cell MDA-MB-231. siRNA knockdown of BRCA-1 or DNA-PKcs, a key gene in non-homologous end joining (NHEJ) DSB repair pathway, also sensitized TNBC cells to 213Bi-Cetuximab. Furthermore, the small molecule inhibitor of DNA-PKcs, NU7441, sensitized BRCA-1 competent TNBC cells to alpha particle radiation. Immunofluorescent staining of γH2AX foci and comet assay confirmed that enhanced RBE is caused by impaired DSB repair. These data offer a novel strategy for enhancing conventional receptor-mediated targeting with an additional, potentially synergistic radiobiological targeting that could be applied to TNBC.

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Lack of functional pRb results in attenuated recovery of mRNA synthesis and increased apoptosis following UV radiation in human breast cancer cells

Cited by 27 publications

References 40 publications

Loss of Robustness and Addiction to IGF1 during Early Keratinocyte Transformation by Human Papilloma Virus 16

Loss of Robustness and Addiction to IGF1 during Early Keratinocyte Transformation by Human Papilloma Virus 16

Interferon regulatory factor-1-induced apoptosis mediated by a ligand-independent fas-associated death domain pathway in breast cancer cells

Targeting Aberrant DNA Double-Strand Break Repair in Triple-Negative Breast Cancer with Alpha-Particle Emitter Radiolabeled Anti-EGFR Antibody

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