Secreted frizzled related protein 1 (SFRP1) functions as an important inhibitor of the Wnt pathway and is a known tumor suppressor gene, which is epigenetically silenced in a variety of
tumors e.g. in
breast cancer. However, it is still unclear how SFRP1 exactly affects the Wnt pathway. Our aim was to decipher SFRP1 involvement in biochemical signaling in dependency of different
breast cancer subtypes and to identify novel SFRP1-regulated genes. We generated SFRP1 over-expressing in vitro
breast cancer models, reflecting the two major subtypes by using basal-like BT20 and
luminal-like HER2-positive SKBR3 cells.
DNA microarray expression profiling of these models revealed that SFRP1 expression potentially modulates
Bone morphogenetic protein- and Smoothened signaling (p<0.01), in addition to the known impact on Wnt signaling. Importantly, further statistical analysis revealed that in dependency of the
cancer subtype model SFRP1 may affect the canonical and non-canonical Wnt pathway (p<0.01), respectively. While SFRP1 re-expression generally mediated distinct patterns of transcriptionally induced or repressed genes in BT20 and SKBR3 cells,
brain derived neurotrophic factor (
BDNF) was identified as a SFRP1 induced gene in both cell lines. Although
BDNF has been postulated as a putative oncogene, the co-regulation with SFRP1 indicates a potential suppressive function in
breast cancer. Indeed, a positive correlation between SFRP1 and
BDNF protein expression could be shown (p<0.001) in primary
breast cancer samples. Moreover, TCGA dataset based analysis clearly underscores that
BDNF mRNA is down-regulated in primary
breast cancer samples predicting a poor prognosis of these patients. In line, we functionally provide evidence that stable
BDNF re-expression in basal-like BT20
breast cancer cells blocks
tumor cell proliferation. Hence, our results suggest that
BDNF might rather mediate suppressive than promoting function in human
breast cancer whose mode of action should be addressed in future studies.