Oestrogen receptor-alpha regulates non-canonical Hedgehog-signalling in the mammary gland.
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-src(Act) 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.
Department of Laboratory Medicine & Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A8.
Nadia
N
Okolowsky
Lombardi Comprehensive Cancer Center, Departments of Oncology and Medicine, Georgetown University, Washington, DC, USA.
Priscilla A
PA
Furth
Department of Laboratory Medicine & Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A8. Electronic address: paul.hamel@utoronto.ca.
Paul A
PA
Hamel
D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D004847:Epithelial Cells; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005348:Fibrocystic Breast Disease / Q000235:genetics; D000077267:Fulvestrant; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009024:Morphogenesis; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010879:Piperazines / Q000494:pharmacology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D000072086:Smoothened Receptor
C412373:AG 1879; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010879:Piperazines; C000606240:Ptch1 protein, mouse; D011720:Pyrazoles; D011743:Pyrimidines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C468919:SANT-1 compound; C465570:Shh protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D000077267:Fulvestrant; D004958:Estradiol; D016392:Proto-Oncogene Proteins pp60(c-src); D048049:Extracellular Signal-Regulated MAP Kinases
Estrogen receptor; Hedgehog pathway; Mammary gland; Mesenchymal dysplasia; Patched1