Estrogen-mediated signaling is differentially affected by the expression levels of Sfrp1 in mammary epithelial cells.

Estrogen has been implicated in breast cancer risk for a variety of reasons including its role in stimulating mammary cell division. Secreted frizzled-related proteins (SFRPs) are a family of Wnt signaling antagonists. Loss of Sfrp1 in mice results in focal ductal epithelial hyperplasias and in humans, loss of SFRP1 is associated with early changes in premalignant breast lesions as well as poor overall survival in patients with early stage breast cancer. Considering that SFRP1 expression is further reduced in ER positive breast cancers when compared with ER negative breast cancers, we chose to determine whether loss of Sfrp1 alters ER signaling. Immunohistochemical analysis revealed that loss of Sfrp1 significantly increased the number of PR and BrdU positve cells in the mammary gland. We further demonstrate that down stream actions of ER-mediated signaling, including cellular proliferation and PR transcription, are elevated in estradiol treated explant cultures derived from Sfrp1(-/-) mice. Additionally, we show that Control explant cultures treated with estradiol exhibit an increase in the mRNA levels of Sfrp1. Finally, we establish that in human mammary epithelial cells with either SFRP1 knocked down (TERT-siSFRP1) and rescued SFRP1 expression (MCF7-SFRP1), estrogen signaling is augmented. Modulation of ER activity appears to be through a mechanism dependent upon Wnt/β-catenin activity. Taken together, our data suggest an important control mechanism by which estrogen signaling is tempered in normal cells and indicates why loss of SFRP1 in early lesions might be a causal change leading to enhanced estrogen-mediated proliferation.