Autocrine/paracrine secreted Frizzled-related protein 2 induces cellular resistance to apoptosis: a possible mechanism of mammary tumorigenesis.

Abnormal regulation of apoptosis and cell proliferation is thought to be involved in tumor formation. The secreted Frizzled-related protein 2 (SFRP2) was detected in primary culture of canine mammary gland tumors but not in normal mammary tissues. Thus, to elucidate the role of SFRP2 in mammary tumorigenesis, we overexpressed SFRP2 in mammary gland tumor and MCF7 cells. The results indicated that SFRP2 is secreted and incorporated into the extracellular matrix (ECM) of the tumor and normal cells. In an attempt to understand the molecular basis underlying the interaction between SFRP2 and ECM, co-immunoprecipitation and cell adhesion assays were carried out. SFRP2 was found to be associated with the fibronectin-integrin protein complex and could promote cell adhesion. DNA fragmentation and caspase 3 activity analyses showed that the susceptibility of the cells to UV-induced apoptosis decreased in the context of SFRP2 overexpression. Upon disruption of the fibronectin-integrin connection, the antiapoptosis activity of SFRP2 was decreased. Moreover, SFRP2 was found to induce tumorous transformation in normal mammary epithelial cells and to inhibit apoptosis in a modified paracrine model. Collectively, our results emphasize the relevance of SFRP2 and ECM in mammary tumorigenesis and provide further insight into the mechanism of SFRP2 action.