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Table 1 Apoptosis avoidance in breast cancer and therapeutic approaches

From: Gene therapy for carcinoma of the breast: Pro-apoptotic gene therapy

Mechanism of apoptosis avoidance Example Normal function Therapeutic strategy References
Increased activity of growth factor receptors IGF-1 receptors are overexpressed and IGF-1 binding protein 3 is decreased IGF-1 binding protein-3 binds to IGF-1, thus blocking the effect of this factor essential for tumor growth; IGF-1 binding protein 3 secretion is induced by p53 Achieve high concentrations of IGF-1 binding protein 3 by intratumoral gene transfer [27,112]
Decreased activity of death receptors TRAIL family Binding of TRAIL to its receptors TRAIL-R1 and TRAIL-R2 induces cell death, whereas TRAIL-R3 and TRAIL-R4 behave as regulatory decoys Achieve high concentrations of TRAIL by intratumoral gene transfer; normal expression of TRAIL-R3 and TRAIL-R4 in normal cells determines a good therapeutic index  
  TNF receptor 1 Mediator in inflammatory and immune responses; it delivers a potent pro-apoptotic signal to the nucleus that is inhibited by NF-κB Achieve high concentrations of TNF by intratumoral gene transfer; the problem is the extreme toxicity on normal cells; more attractive is to inhibit NF-κB (eg by gene delivery of IκB) [129]
  Fas is downregulated Determines sensitivity to CTLs; Fas is induced by p53; Fas ligand expression correlates with tumor grade, possibly contributes to local deletion of lymphocytes, and has a role in tumor invasion through Fas+ stroma Achieve high concentrations of Fas ligand by intratumoral gene transfer; the problems are the toxicity on normal cells and the risk of endowing the tumor cell with more invasiveness and resistance to the immune system [130]
Increased activity of survival proteins HER-2/neu Overexpression of this growth factor receptor contributes to the malignant phenotype Inhibit exogenous survival signals by a single chain antibody: scFv anti-erbB-2 [131]
  Bcl-2 and functional analogs Blocks apoptosis triggered by several factors. Early in tumor development, Bcl-2 may rescue cells undergoing lethal mutations, and thus favor the accumulation of further genetic damage. Later, when other oncogenes are activated and Bax is lost, the loss of Bcl-2 may confer an additional growth advantage Block by antisense or intracellular single chain antibodies: scFv anti-Bcl-2 [132]
  NF-κB Activates transcription of IAPs and of its own activators Inhibit this inhibitor of exogenous death signals (eg by gene delivery of IκB) [129]
  Survivin Member of the IAP family; overexpressed in most tumors; inhibits apoptosis by binding to caspases Block by antisense, intracellular single-chain antibodies, etc [133]
  HSP-70 Inhibits apoptosis by binding to activated caspases; prognostic factor in breast cancer; correlates with shorter disease-free survival, increased cell Block by antisense proliferation, and poor differentiation, as well as with lymph node metastasis [134]
Decreased activity of apoptosis executioners Bax Effects apoptosis; acts by inducing opening of mitochondrial permeability transition pore, and cytochromec release; active even in the presence of Bcl-2 and independently of p53 Achieve high concentrations of Bax by intratumoral gene transfer [eg Ad/Bax (proof-of-principle in ovarian cancer)]; induce Bax by upstream positive regulators, such as mda-7 [126,135,136]
  Bcl-Xs Induces apoptosis probably without requiring dimerization and even in the presence of Bcl-2 Achieve high concentrations of Bcl-Xs by intratumoral gene transfer (eg Ad/Bcl-Xs) [3,137,138,139]
  Caspase-7 Member of the caspase family of proteins with an effector role in the activation cascade Achieve high concentrations of caspase by intratumoral gene transfer (proof of principle shown in prostate cancer)  
  Apoptin This is a chicken anemia virus-derived protein that induces apoptosis in transformed cells, but not in normal, diploid cells Induce intratumoral or systemic levels of apoptin (eg with Ad/apoptin) [140,141]
Deranged activity of checkpoint controls and DNA repair p53 Induces cell cycle stop or apoptosis when DNA damage is detected; frequently mutated in breast cancer; increases the function of Bcl-2 and FasL Restore levels of p53 (eg by Ad/p53); limited by inactivation of wild-type p53 and dependence on multiple cofactors [84,85,86,87,88,89,90]
  BRCA1 Involved in DNA damage checkpoints; possibly has a pivotal role in maintaining stability of the genome; BRCA1 induces apoptosis Gene transfer of BRCA1; limitation of lacking a means for local amplification of effect [142]
  PML The promyelocytic leukemia gene (PML) is a growth and transformation suppressor Delivery of PML via an adenoviral vector has shown induction of massive apoptotic death in in vivo animal models of breast cancer [143]
Combination treatment Various   Association with chemotherapy or radiotherapy; blocks for apoptosis are removed, allowing the conventional treatment to [4**,6,144]
  1. Ad, adenovirus; CTL, cytotoxic T lymphocyte; HER, human epidermalgrowth factor receptor-related gene; HSP, heat shock protein; IAP, inhibitor ofapoptosis protein; IGF, insulin-like growth factor; NF-κB, nuclearfactor-κB; TNF, tumor necrosis factor; TRAIL, TNF-relatedapoptosis-inducing ligand.