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 estrogen receptor alpha (Esr1) 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 Rspo1 results in decreased Esr1 expression and reduced mammary side branches. In contrast, luminal cells-specific knockout of Wnt4, while attenuating basal cell Wnt/β-catenin signaling activities, enhances Esr1 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.
Highlights
Estrogen and progesterone are the main players in mammary development and the progression of breast cancers (Hilton et al, 2018; Macias and Hinck, 2012)
Transcriptome and Gene ontology (GO) analysis identified enrichment of various features, including estrogen receptor activity (Figure 1a and b). qPCR analysis verified that the expression of ERa signaling target genes, including Pgr, Ctsd1 (Cathepsin D1) (Meneses-Morales et al, 2014), and Wisp2 (Zhang et al, 2012b) are enhanced in the presence of RSPO1 (Figure 1—figure supplement 1b)
We found that in this ER+ luminal cell culture system, RSPO1 elevated the expression of Esr1 and its target Pgr to a level comparable with E2 treatment
Summary
Estrogen and progesterone are the main players in mammary development and the progression of breast cancers (Hilton et al, 2018; Macias and Hinck, 2012). Our recent study reported the enhanced Rspo expression in estrus, a stage with high estrogen signaling activity (Cai et al, 2020). Another role of Rspo may exist besides maintaining basal stem cells. We provide evidence that Rspo promotes ERa (Esr1) expression in luminal cells of the mammary gland. This action of Rspo is through activating G-protein coupled cAMP/ PKA pathway, while independent of Wnt/b-catenin signaling. Our data reveal a novel Wnt-independent role of Rspo, and a new upstream regulatory axis for Esr expression
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