**7. Acknowledgements**

This book chapter project was funded by a Fundamental Research Grant Scheme (FRGS) Fasa 2/2010 (203/CIPPM/6711162) from the Ministry of Higher Education (MoHE), Malaysia. The author also thanks the technical support of all members at the Division of Oncology and Hematology, Charité Campus Mitte, Humboldt University of Berlin, Germany.

### **8. References**

Al-Hajj, M.; Wicha, M.S.; Benito-Hernandez, A.; Morrison, S.J. & Clarke, M.F. (2003) Prospective identification of tumorigenic breast cáncer cells. *Proc. Natl. Acad. Sci. USA*, 100, 3983-3988.

cells) and CD105- (epithelial cells) MDA-MB-231 cells. The invasion rate of the drugtreated CD105+ and CD105- MDA-MB-231 will then be determined using the Matrigel invasion assay. The mRNA and protein expression levels of the ECM degradationassociated molecules in the drug-treated CD105+ and CD105- MDA-MB-231 cells will also be assessed using real-time PCR and Western Blotting, respectively, and the gelatinase activities in the conditioned medium of drug-treated CD105+ and CD105- MDA-MB-231 cells will be investigated using ELISA. The proposed project that will utilise cell separation and isolation techniques to study the breast cancer cell invasion is a new area of cancer research in the institute of my home country. The previous research projects regarding the MDA-MB-231 cell invasion and metastasis were related to drug treatments, the effects of herbal and plant extracts, and the understanding of a gene or protein activity in cancer cells and animal models. However, the approaches to study the cancer cell invasion and metastasis by isolating or withdrawing the mesenchymal-like breast cancer cells (CD105+) from the MDA-MB-231 cell population using cell separation or isolation have not been demonstrated. Therefore, this project may establish a new fundamental cancer research and new research topic in my institute. This study may also lay a research foundation that is focused on the inhibition of invasion for the ER-negative human breast cancer cells. I also believe that, by targeting the mesenchymal-like phenotype in the MDA-MB-231 subpopulation, the invasion rate of the ER-negative human breast cancer

All of the results mentioned above show that the MDA-MB-231 cells likely display a mesenchymal-like phenotype that facilitates the cells to be a highly metastatic breast cancer cell line. However, a deeper understanding of the cell morphology, gene expression and intracellular mechanisms and pathways of the cancer cells that can explain the interaction between mesenchymal-like and epithelial cells in the MDA-MB-231 cells is warranted. By targeting this phenotype, the metastatic potency and the growth of the cancer cells may be controlled or effectively reduced. A potential anticancer drug can also be identified to treat both human breast cancers and other malignancies. Perhaps, withdrawing the progenitor factor from a tumour may serve as a potential machinery target in cell-mediated therapy for

This book chapter project was funded by a Fundamental Research Grant Scheme (FRGS) Fasa 2/2010 (203/CIPPM/6711162) from the Ministry of Higher Education (MoHE), Malaysia. The author also thanks the technical support of all members at the Division of Oncology and Hematology, Charité Campus Mitte, Humboldt University of Berlin,

Al-Hajj, M.; Wicha, M.S.; Benito-Hernandez, A.; Morrison, S.J. & Clarke, M.F. (2003)

Prospective identification of tumorigenic breast cáncer cells. *Proc. Natl. Acad. Sci.* 

cells can be easily monitored and controlled.

**6. Conclusion** 

human breast cancer.

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**7. Acknowledgements** 

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**19** 

*Italy* 

**p130Cas and p140Cap as the Bad and Good** 

P. Di Stefano, M. del P. Camacho Leal, B. Bisaro, G. Tornillo, D. Repetto, A. Pincini, N. Sharma, S. Grasso, E. Turco, S. Cabodi and P. Defilippi

Breast cancer is an aggressive malignancy affecting a large woman population. Even though important progress have been made in providing new therapies to treat this neoplasia, our knowledge on the mechanisms underlying the transformation of breast epithelial cells in tumor cells is still superficial. The neoplastic phenotype results from the alteration of multiple cellular signaling mechanisms controlling proliferation, survival and invasiveness. Moreover, the prognosis of breast cancer patients is tightly correlated with the degree of spread beyond the primary tumor. However the mechanisms by which epithelial tumor cells escape from the primary tumor and colonize a distant site are not entirely understood. In this chapter we will discuss recent data on the relevance of p130Cas and p140Cap adaptor molecules in breast cancer signalling related to the acquirement on invasive properties. Due to the presence of adaptor modules, these proteins create signalling platforms proximal to plasma membrane cell surface receptors, such as integrins and growth factor receptors. p130Cas and p140Cap exert opposite regulation on cell signalling. Indeed p130Cas has been shown to increase survival, proliferation and migration of normal and transformed cells either in response to cell matrix adhesion or to hormones and growth factors. Moreover, p130Cas has been recently linked to resistance to breast cancer treatments, revealing its potential use as a novel therapeutic target. Instead, p140Cap behaves as a potent negative regulator of signalling pathways leading to cancer cell proliferation and migration. In this chapter, we will discuss the increasing evidence that highlight the importance of these

It is well established that to migrate and to invade a cell needs to detach from its neighbors, i.e. adjacent cells in an epithelium, to extend lamellipodia and filopodia from the leading edge and to create new dynamic adhesions, which form and rapidly disassemble at the base of protrusions (Mitra *et al.*, 2005; Ridley *et al.*, 2003). Cell invasion also requires the release or activation of proteases that degrade the extracellular matrix (ECM) and allows cells to sort out from the basal lamina invading surrounding tissues (Eliceiri *et al.*, 2002). Under physiological conditions cell motility and invasion are tightly controlled by a complex interplay among cell-cell, cell matrix and growth factors receptors resulting in the maintenance of the architectural integrity of human tissues. This subtle regulation is lost in

**1. Introduction** 

adaptor proteins in breast cancer.

**Guys in Breast Cancer Cell Progression** 

*Molecular Biotechnology Center, Università di Torino, Torino* 

**to an Invasive Phenotype** 

Zinzalla, G.; Haque, M.R.; Basu, B.P.; Anderson, J.; Kaye, S.L.; Haider, S.; Hasan, F.; Antonow, D.; Essex, S.; Rahman, K.M.; Palmer, J.; Morgenstern, D.; Wilderspin, A.F.; Neidle, S. & Thurston, D.E. (2010) A novel small-molecule inhibitor of IL-6 signalling. *Bioorg. Med. Chem. Lett.,* 20, 7029-7032.
