The role of integrin ±2²1 in breast cancer metastasis to bone

Abstract

The ability of cells to adhere to each other and to the extracellular matrix is essential for the formation of tissues and organs. Among the different classes of adhesion molecules, integrins stand out because they bind to proteins associated with cytoskeletal linkage and signaling molecules, promoting mechanical signals. Besides these adhesion molecules are involved in normal cellular functions, playing an important role in pathological processes such as metastasis progression which metastatic cells released from the primary tumor attach to secondary organs. One of the most common tumors in women is breast cancer, often characterized by skeletal metastases. One possibility that could explain the selectivity to the bone is that tumor cells express surface molecules that facilitate their attachment to proteins present in the extracellular matrix of bone, mainly collagen. Recent studies have shown a relationship between the ±2²1 integrin, a receptor for collagen, and the development of bone metastases in prostate cancer. In this context, the understanding of the mechanisms by which this integrin promotes tumor may provide an important target for pharmacological intervention in the prevention of metastases. The main hypothesis of this proposal is that ±2²1 integrin has an important effect on tumor progression from breast cancer to bone tissue. We propose the following specific objectives to test this hypothesis. 1) Evaluation of the effect of ±2²1 integrin silencing and overexpression on the homeostasis of bone tissue during breast cancer metastasis in vivo: we will use an established model of bone metastasis in mice (intracardiac), which will be carried out in the presence of a selective ±2²1 ligand as control. The outcomes will be: quantitation of bone volume and quality by micro-CT, evaluation of bone histomorphometry and analysis of transfected cells in tumor progression by fluorescence imaging in vivo. 2) Description of the role of ±2²1 signaling on the modulation of cellular adhesion in bone metastasis of breast cancer: we will evaluate the presence of focal adhesion kinase (FAK) protein in transfected MDA-MB-231 cell line by immunofluorescent staining. In addition, Western Blot and real time PCR will be performed to confirm the relationship between ±2²1 and FAK expression.