**4. Acknowledgements**

The ''Ligue contre le Cancer" (54, 55, 57 and 88 Departmental committees) is acknowledged for its nancial support. E.B is recipient of an AFR grant of the National Research Fund, Luxembourg.

### **5. References**

34 Breast Cancer – Focusing Tumor Microenvironment, Stem Cells and Metastasis

which biology may significantly differ from human one (Kim *et al.* 2004a). Furthermore, in humans, the immune system plays an important role in the fight against tumour, whereas in

The xenograft model has some limitations but is the most accomplished of all models

Besides the xenografts, there are also murine models which can develop tumours spontaneously or under the influence of inducing compounds (Russo & Russo 1996). Although the achievement of these models is easy, their use is largely debated because of their relevance to the clinical situation. Indeed, murine breast cancers are most often caused by viral infections and are not hormone dependent, whereas a considerable proportion of human cancers are oestrogen dependent. To date there is no evidence suggesting a viral induction of breast cancer in humans. The biology of spontaneous rodent tumours differs from the human ones. The size, the oncogenic targets or the degree of maturation and differentiation of cells differ between the two species, making them hardly comparable.

In this chapter, we described the main models used in breast cancer research in order to obtain results of high scientific quality. In summary, we can say that BCCL models allow repeatable experiments with simple material and methods. They are inevitable models for basic studies and mechanistic explorations, but their use is still controversial owing to their approximate representativeness of breast tumours in human and to the existence of

Cultures of cancerous tissues preserve the tumour architecture and the cell diversity of a tumour but this model suffers of limited reproducibility and cannot be easily maintained for a long time. Co-culture systems offer an alternative with reproducible long term culture systems, and offer the possibility to study the relations between different types of cells in tumour, but this model suffers from the same controversies as BCCL as it mainly relies on

3-dimensional systems allow the mimicking of the tumour architecture and microenvironment, but very few cell lines are able to form spheroids under specific

Considering the advantages and drawbacks of these models, the xenografts appear to be good alternative models as they enable to take into account the tumour structure, its microenvironment, the role of the metabolism and they preserve the cell diversity of the tumour. But as other models, they also have drawbacks principally due to the metabolic and physiological differences existing between human and rodents, and to the fact that the role of the immune system against tumour is not taken into account with the immunodeficient

Application of the 3Rs principle leaded to the development of all these models, but we showed that none of them is sufficient by itself and able to perfectly mimic breast cancer in human. However it clearly appears that all these models are essential to accumulate data

The ''Ligue contre le Cancer" (54, 55, 57 and 88 Departmental committees) is acknowledged for its nancial support. E.B is recipient of an AFR grant of the National Research Fund,

xenografts models the immune system is totally absent.

**3. Conclusion** 

misidentified cell lines.

rodent models used for xenografts.

and information to fight breast cancer.

**4. Acknowledgements** 

Luxembourg.

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conditions.

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**3** 

**Insulin-Like-Growth Factor-Binding-Protein 7:** 

The insulin-like growth factor (IGF) system has been shown to have an integral role in normal growth and development, and in the pathophysiology of various cancers. The IGF system is comprised of a series of circulating ligands (IGF-1, IGF-2), transmembrane receptor tyrosine kinases (IGF-1R, IGF-2R, and the insulin receptor (IR), high affinity ligandbinding proteins (IGFBP1-6), IGFBP proteases, and several low affinity IGFBP-related

There are two key circulating ligands, IGF-1 and IGF-2, which share approximately 50% structural homology with insulin[2]. IGF-1 is produced primarily in the liver in response to circulating levels of growth hormone(GH) [3]. IGF-1 and IGF-2 are highly homologous small peptide hormones of approximately 7 kDa molecular mass, which are important mitogens that affect cell growth and metabolism [2]. IGFs interact with specific cell surface receptors, designated type I and type 2 IGF receptors, and can also interact with insulin receptor (IR). The type I IGF receptor (IGF-1R) is a transmembrane heterotetramer consisting of 2 extracellular alpha subunits and two intracellular beta subunits linked by disulfide bonds (fig 1). The intracellular component of IGF-1R has intrinsic tyrosine kinase activity that requires ligand binding for activation [4]. The IGF-1R and the IR share approximately 60% homology which allows them to form hybrid receptors [5]. As a result of this homology, IGF-1R can be activated not only by IGF-1 but also IGF-2 and insulin, although the affinity of IGF-1R for IGF-2 and insulin is approximately 10 fold and 1000 fold lower than for IGF-1, respectively [6]. The type 2 IGF receptor (IGF-2R), which is identical to the cationindependent mannose-6-phosphate receptor, binds IGF-2 with 500 fold increased affinity over IGF-1[7]. IGF-2R does not bind insulin. Most of the biological activity of IGF-2 is thought to be mediated through binding IGF-1R[7]. IGF-2 is known to function primarily as a scavenger receptor, regulating circulating IGF-II levels through internalization and

proteins (IGFBP-rp1 to 10) that work in unison to regulate cell growth [1].

**1. Introduction** 

degradation [7].

**1.1 The insulin-like growth factor (IGF) system** 

*Division of Molecular and Cellular Biology, Sunnybrook Research Institute, Department of Anatomic Pathology, Sunnybrook Health Sciences Centre,* 

**An Antagonist to Breast Cancer** 

*Department of Laboratory Medicine and Pathobiology,* 

Tania Benatar, Yutaka Amemiya,

Wenyi Yang and Arun Seth

*University of Toronto, ON,* 

*Canada* 

