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.