Oestrogen receptor-alpha regulates non-canonical Hedgehog-signalling in the mammary gland

Abstract

Mesenchymal dysplasia (mes) mice harbour a truncation in the C-terminal region of the Hh-ligand receptor, Patched-1 (mPtch1). While the mes variant of mPtch1 binds to Hh-ligands with an affinity similar to that of wild type mPtch1 and appears to normally regulate canonical Hh-signalling via smoothened, the mes mutation causes, among other non-lethal defects, a block to mammary ductal elongation at puberty. We demonstrated previously Hh-signalling induces the activation of Erk1/2 and c-src independently of its control of smo activity. Furthermore, mammary epithelial cell-directed expression of an activated allele of c-src rescued the block to ductal elongation in mes mice, albeit with delayed kinetics. Given that this rescue was accompanied by an induction in estrogen receptor-alpha (ERα) expression and that complex regulatory interactions between ERα and c-src are required for normal mammary gland development, it was hypothesized that expression of ERα would also overcome the block to mammary ductal elongation at puberty in the mes mouse. We demonstrate here that conditional expression of ERα in luminal mammary epithelial cells on the mes background facilitates ductal morphogenesis with kinetics similar to that of the MMTV-c-srcAct mice. We demonstrate further that Erk1/2 is activated in primary mammary epithelial cells by Shh-ligand and that this activation is blocked by the inhibitor of c-src, PP2, is partially blocked by the ERα inhibitor, ICI 182780 but is not blocked by the smo-inhibitor, SANT-1. These data reveal an apparent Hh-signalling cascade operating through c-src and ERα that is required for mammary gland morphogenesis at puberty.

Hedgehog Signaling in the Maintenance of Cancer Stem Cells

“…Whilst canonical Hh signaling culminates in Gli-mediated transcription, there is growing evidence for “non-canonical” Hh signaling mechanisms. In this case, signaling may occur via Hh signaling components in alternative ways to the canonical paradigm [ 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ]. Since a role for non-canonical Hh signaling in CSC maintenance is yet to be elucidated, this review will focus on the canonical pathway.…”

Activities of the Cytoplasmic Domains of Patched-1 Modulate but Are Not Essential for the Regulation of Canonical Hedgehog Signaling

“…However, in the skin of mes mice, where precocious hair follicle development occurs, altered canonical Hh signaling was not observed (38). Similarly, no increase in canonical Hh signaling was seen in epithelial cells of the mammary gland despite development of this skin appendage at puberty being blocked by the mes mutation (39,40). Indeed, Hh signaling in mammary epithelial cells appears to require a cascade that involves estrogen receptor-␣ and c-src rather than the canonical signaling pathway operating through Smo (39,40).…”

“…Similarly, no increase in canonical Hh signaling was seen in epithelial cells of the mammary gland despite development of this skin appendage at puberty being blocked by the mes mutation (39,40). Indeed, Hh signaling in mammary epithelial cells appears to require a cascade that involves estrogen receptor-␣ and c-src rather than the canonical signaling pathway operating through Smo (39,40). Despite these apparent tissue-specific effects of truncating the C terminus of Ptch1, wild-type Ptch1 and mes repress Hh signaling similarly when introduced into Ptch1-deficient MEFs (27,38).…”

Sonic Hedgehog Signaling in Organogenesis, Tumors, and Tumor Microenvironments

“…During puberty, ductal morphogenesis is affected by canonical and non-canonical SHH signaling, for which type I non-canonical SHH signaling plays an essential role [4,111]. During puberty, the elongation of the terminal buds is affected via activation of cellular Src kinase (c-Src), estrogen receptor alpha (ERα), and extracellular signal-regulated kinase (ERK) cascades in mammary luminal epithelial cells [120][121][122]. At this stage, a decrease of the expression of SHH ligands GLI1, GLI2, GLI3, and PTCH1 in the mature mammary gland is also found [114,118,123].…”