title: The nicotinic acetylcholine receptor-mediated reciprocal effects of the tobacco nitrosamine NNK and SLURP-1 on human mammary epithelial cells.
abstract: Recent research has demonstrated that the nicotinergic signaling network of mammary epithelium can both mediate the physiological control of normal breast epithelial cells (BECs) and exhibit tumor-promoting effects on malignant BECs. Therefore, mammary nicotinic acetylcholine (ACh) receptors (nAChRs) may become a specific target for novel anti-breast cancer therapies. Toward this goal, we investigated the difference in the ACh receptor repertoires between normal and malignant BECs, determined effects of nicotinic ligands on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-dependent activation of ERK1/2 and tumorigenic transformation of MCF10A cells, and characterized reciprocal effects of NNK and SLURP (secreted mammalian Ly-6/urokinase plasminogen activator receptor related protein-1)-1 on the expression of nAChR subunits and several oncogenes and tumor-suppressing genes in BECs. Both the non-malignant MCF10A and malignant MCF7 breast cells expressed α3, α5, α7, α9, α10, β1, β2, γ, δ and ε nAChR subunits and M(1), M(3), M(4) and M(5) muscarinic receptor subtypes. The malignancy was associated with expression of α1, α4 and β4 nAChR subunits and M(2) subtype. Malignant transformation of BECs was also associated with overexpression of α7-, and α9-made nAChRs. NNK upregulated ERK1/2 phosphorylation, stimulated expression of the gene encoding the tumor-promoter HGF, downregulated expression of the tumor suppressor gene CDKN2A, and induced tumorigenic transformation of MCF10A cells. Compared to the canonical nAChR antagonists, SLURP-1 showed the highest ability to abolish the nAChR-mediated effects of NNK in both cell-signaling and cell-transformation assays and reversed many effects of NNK on gene expression. SLURP-1 also markedly upregulated the tumor suppressor genes CDKN2B, RUNX3 and TP73. Altogether, the obtained results provided new insight into the molecular mechanisms of nAChR-mediated oncogenic effects of NNK on BECs and demonstrated the ability to abolish or reverse these effects by SLURP-1.
authors.affiliation: Department of Dermatology, University of California, Irvine, CA, USA.
authors.forename: Mina
authors.initials: M
authors.lastname: Kalantari-Dehaghi
authors.affiliation: Department of Molecular Biology, University of California, Irvine, CA, USA; Division of Biomedical Sciences, University of California, Riverside, CA, USA.
authors.forename: Erinn A
authors.initials: EA
authors.lastname: Parnell
authors.affiliation: Department of Molecular Biology, University of California, Irvine, CA, USA; Department of Bioengineering University of California, Berkeley, CA, USA.
authors.forename: Tara
authors.initials: T
authors.lastname: Armand
authors.affiliation: Department of Molecular Biology, University of California, Irvine, CA, USA.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Bernard
authors.affiliation: Department of Dermatology, University of California, Irvine, CA, USA; Department of Biological Chemistry, University of California, Irvine, CA, USA; Cancer Center and Research Institute, University of California, Irvine, CA, USA. Electronic address: sgrando@uci.edu.
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Grando
mesh_terms: D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D009602:Nitrosamines / Q000494:pharmacology*; D010766:Phosphorylation; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
chemical_list: D000950:Antigens, Ly; D009602:Nitrosamines; D011978:Receptors, Nicotinic; C048963:SLURP1 protein, human; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D048049:Extracellular Signal-Regulated MAP Kinases; D014568:Urokinase-Type Plasminogen Activator
keywords: Gene expression; MCF-10A cells; MCF-7 cells; NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone); Nicotinic acetylcholine receptors, proliferation, breast cancer; SLURP (secreted mammalian Ly-6/urokinase plasminogen activator receptor related protein-1)-1 and -2