Cyr61, a member of the CCN (CTFG, CYR61/NOV) family of factors that modulate the growth of cells, is also capable of increasing the blood supply to the tumor cells, acting as an "angiogenic factor" and intervening in the development and progression of breast carcinomas. We have recently shown that Cyr61 is highly expressed in invasive and metastatic human breast cancer cells. Accordingly, elevated levels of Cyr61 in breast cancer are associated with more advanced disease. Unfortunately, the exact mechanisms by which Cyr61 promotes an aggressive breast cancer phenotype are still largely unknown.

We present data suggesting that Cyr61 function may play a major role in the progression of breast carcinomas that are regulated via either hormonal or growth factor machinery. We also emphasize the functional significance of the molecular connection of Cyr61 and its integrin receptor alphavbeta3 enhancing breast cancer aggressiveness. Moreover, we present a number of experimental evidences that establish a novel role for Cyr61 in the resistance of human breast cancer cells against chemotherapy that induces cell death. Interestingly, the induction of breast cancer cell death is through the blockage of ligand/receptor interaction, which is usually very specific and it is outside the cells in the extracellular compartment, thereby preventing the lack of specificity. By preventing Cyr61 binding to its receptor, the integrin alphavbeta3, using highly specific compounds, we not only achieve inhibition of cell growth but also revert the resistance to chemotherapeutic drugs such as Taxol. The data will allow a new major place of Cyr61/alphavbeta3 autocrine-paracrine signaling within both angiogenesis and breast cancer progression, which would allow the development and the understanding of a dual anti-angiogenic and antitumor strike with a single drug.

We propose to develop a preclinical trial using these compounds, initially in vitro utilizing many more models and then in vivo. We will also assess the mechanism by which Cyr61 induces Taxol resistance. Finally, we will determine whether Cyr61 expression could predict resistance to Taxol or whether increased Cyr61 expression is a result of acquisition of Taxol resistance. Altogether, this is the first time, to the best of our knowledge, that Cyr61 has been implicated in the increase of alphavbeta3 expression in breast cancer epithelial cells. This is of extreme importance and very novel since this approach indicates that activation of Cyr61-alphavbeta3 signaling network could drive breast cancer cells to escape hormonal requirements, providing compensatory survival pathways that ultimately allow the appearance of breast cancer chemoresistance.