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Background  Secreted frizzled-related proteins (SFRPs) are a family of proteins that block the Wnt signaling pathway and loss of Sfrp1 expression is observed in breast cancer. The molecular mechanisms by which obesity contributes to breast tumorigenesis are not well defined, but involve increased inflammation. Mice deficient in Sfrp1 show enhanced mammary gland inflammation in response to diet induced obesity (DIO). Furthermore, mammary glands from  Sfrp1    −/−    mice exhibit increased Wnt signaling, decreased cell death responses, and excessive hyper branching. The work described here was initiated to investigate whether obesity exacerbates the aforementioned pathways, as they each play a key roles in the development of breast cancer.    Findings  Wnt signaling is significantly affected by DIO and  Sfrp1    −/−    loss as revealed by analysis of  Myc  mRNA expression and active β-catenin protein expression. Furthermore,  Sfrp1    −/−    mice fed a high fat diet (HFD) exhibit an increase in mammary cell proliferation. The death response is also impaired in the mammary gland of  Sfrp1    −/−    mice fed a normal diet (ND) as well as a HFD. In response to γ-irradiation, mammary glands from  Sfrp1  −/−  mice express significantly less  Bax  and  Bbc3  mRNA, caspase-3 positive cells, and p53 protein. The expression of  Wnt4  and  Tnfs11  are critical for normal progesterone mediated mammary gland development and in response to obesity,  Sfrp1  −/−  mice express significantly more  Wnt4  and  Tnfs11  mRNA expression. Evaluation of progesterone receptor (PR) expression showed that DIO increases the number of PR positive cells.    Conclusions  Our data indicate that the expression of  Sfrp1  is a critical factor required for maintaining appropriate cellular homeostasis in response to the onset of obesity.

The effects of diet induced obesity on breast cancer associated pathways in mice deficient in SFRP1