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 | |
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 | Â |
|  | 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] |
| Â | 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] |
| Â | 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] |
| Â | 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] |
| Â | 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 | |
| Â | 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) | |
| Â | 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) | Â |
| Â | 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) | |
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 | |
| Â | 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] |
| Â | 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 | Â | Association with chemotherapy or radiotherapy; blocks for apoptosis are removed, allowing the conventional treatment to |