A novel function of R-spondin1 in regulating estrogen receptor expression independent of Wnt/β-catenin signaling.

Abstract

R-spondin1 (Rspo1) has been featured as a Wnt agonist, serving as a potent niche factor for stem cells in many tissues. Here we unveil a novel role of Rspo1 in promoting <i>estrogen receptor alpha (Esr1)</i> expression, hence regulating the output of steroid hormone signaling in the mouse mammary gland. This action of Rspo1 relies on the receptor Lgr4 and intracellular cAMP-PKA signaling, yet is independent of Wnt/β-catenin signaling. These mechanisms were reinforced by genetic evidence. Luminal cells-specific knockout of <i>Rspo1</i> results in decreased <i>Esr1</i> expression and reduced mammary side branches. In contrast, luminal cells-specific knockout of <i>Wnt4</i>, while attenuating basal cell Wnt/β-catenin signaling activities, enhances <i>Esr1</i> expression. Our data reveal a novel Wnt-independent role of Rspo1, in which Rspo1 acts as a bona fide GPCR activator eliciting intracellular cAMP signaling. The identification of Rspo1-ERα signaling axis may have a broad implication in estrogen-associated diseases.