2096

Cyr61 (recently termed CCN1) belongs to the CCN protein family of regulatory factors (CCN {CYR61 [Cystein-rich61], CTGF [connective tissue growth factor] and NOV [Nephroblastoma overexpressed]}). These regulatory factors have been involved in multiple aspects of cell survival, proliferation and differentiation. We and others have associated the anomalous expression of CCN1 to tumorigenesis. One of the more salient aspects of CCN1 is its multimodular architecture that allows physical interaction with different signaling proteins and integrins such as αvβ3. αvβ3 overexpression is a poor prognostic indicator for breast cancer. Our recent studies have revealed that overexpressing CCN1 promotes constitutive Estrogen Receptor (ER) transcriptional activation in breast cancer cells. Interestingly, we further demonstrated that CCN1 is located in the nucleus. To determine whether overexpression of CCN1 in breast cancer cells promotes the activation of specific transcription factors (TF) we utilize the TranSignal™ Protein/DNA arrays (Panomics) and determined the patterns of activated TF when the membranes were treated with nuclear extracts derived from MCF-7 cells overexpressing: 1) the full length cDNA of CCN1 (MCF-7/CCN1), 2) the point mutant cDNA of CCN1, which prevents its binding to αvβ3 (MCF-7/D125A), 3) wild type retroviral vector the pBabe (MCF-7/Pbabe). Interesting overexpression of CCN1 induced significantly the transcriptional activity of the Polyomavirus enhancer activator 3 (PEA3), a member of the Ets family of transcription factors and of the nuclear factor of activated T cells (NFAT). Both of these factors were indeed correlated with the ability of CCN1 to induce tumor progression and survival. More significantly, we demonstrated that while signaling of CCN1 through αvβ3 induces transcriptional activation of PEA3 and NFAT, disruption of the CCN1: αvβ3 prevents the transcriptional activation. Our data, demonstrates for the first time, that CCN1 apparently plays a key role in the nucleus. These data suggest a significant role of CCN1:αvβ3 autocrine and paracrine interaction to promote, breast cancer survival, tumor progression and metastasis via activation of a series of events leading to activation of the αvβ3 signalling pathway, and which also reveals CCN1-nuclear localization and the specific induction of transcription factors that apparently control the progression of subset of breast carcinomas which highly express CCN1.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA