title: Estrogen, SNP-Dependent Chemokine Expression and Selective Estrogen Receptor Modulator Regulation.
abstract: We previously reported, on the basis of a genome-wide association study for aromatase inhibitor-induced musculoskeletal symptoms, that single-nucleotide polymorphisms (SNPs) near the T-cell leukemia/lymphoma 1A (TCL1A) gene were associated with aromatase inhibitor-induced musculoskeletal pain and with estradiol (E2)-induced TCL1A expression. Furthermore, variation in TCL1A expression influenced the downstream expression of proinflammatory cytokines and cytokine receptors. Specifically, the top hit genome-wide association study SNP, rs11849538, created a functional estrogen response element (ERE) that displayed estrogen receptor (ER) binding and increased E2 induction of TCL1A expression only for the variant SNP genotype. In the present study, we pursued mechanisms underlying the E2-SNP-dependent regulation of TCL1A expression and, in parallel, our subsequent observations that SNPs at a distance from EREs can regulate ERα binding and that ER antagonists can reverse phenotypes associated with those SNPs. Specifically, we performed a series of functional genomic studies using a large panel of lymphoblastoid cell lines with dense genomic data that demonstrated that TCL1A SNPs at a distance from EREs can modulate ERα binding and expression of TCL1A as well as the expression of downstream immune mediators. Furthermore, 4-hydroxytamoxifen or fulvestrant could reverse these SNP-genotype effects. Similar results were found for SNPs in the IL17A cytokine and CCR6 chemokine receptor genes. These observations greatly expand our previous results and support the existence of a novel molecular mechanism that contributes to the complex interplay between estrogens and immune systems. They also raise the possibility of the pharmacological manipulation of the expression of proinflammatory cytokines and chemokines in a SNP genotype-dependent fashion.
authors: Division of Clinical Pharmacology (M.-F.H., M.L., L.W., R.M.W.), Department of Molecular Pharmacology and Experimental Therapeutics, Division of Rheumatology (M.-F.H., T.B.), Department of Medicine, Division of Biomedical Statistics and Informatics (K.R.K.), Department of Health Sciences Research, and Division of Medical Oncology (M.P.G., J.N.I.), Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905; Division of Hematology/Oncology (P.E.G.), Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard University, Boston, Massachusetts 02114; National Cancer Institute of Canada Clinical Trials Group (L.E.S.), Kingston, Ontario, Canada K7L 3N6; and RIKEN Center for Integrative Medical Science (M.K.), Yokohama 230-0045, Japan.
authors: Ming-Fen
authors: MF
authors: Ho
authors: Division of Clinical Pharmacology (M.-F.H., M.L., L.W., R.M.W.), Department of Molecular Pharmacology and Experimental Therapeutics, Division of Rheumatology (M.-F.H., T.B.), Department of Medicine, Division of Biomedical Statistics and Informatics (K.R.K.), Department of Health Sciences Research, and Division of Medical Oncology (M.P.G., J.N.I.), Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905; Division of Hematology/Oncology (P.E.G.), Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard University, Boston, Massachusetts 02114; National Cancer Institute of Canada Clinical Trials Group (L.E.S.), Kingston, Ontario, Canada K7L 3N6; and RIKEN Center for Integrative Medical Science (M.K.), Yokohama 230-0045, Japan.
authors: Tim
authors: T
authors: Bongartz
authors: Division of Clinical Pharmacology (M.-F.H., M.L., L.W., R.M.W.), Department of Molecular Pharmacology and Experimental Therapeutics, Division of Rheumatology (M.-F.H., T.B.), Department of Medicine, Division of Biomedical Statistics and Informatics (K.R.K.), Department of Health Sciences Research, and Division of Medical Oncology (M.P.G., J.N.I.), Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905; Division of Hematology/Oncology (P.E.G.), Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard University, Boston, Massachusetts 02114; National Cancer Institute of Canada Clinical Trials Group (L.E.S.), Kingston, Ontario, Canada K7L 3N6; and RIKEN Center for Integrative Medical Science (M.K.), Yokohama 230-0045, Japan.
authors: Mohan
authors: M
authors: Liu
authors: Division of Clinical Pharmacology (M.-F.H., M.L., L.W., R.M.W.), Department of Molecular Pharmacology and Experimental Therapeutics, Division of Rheumatology (M.-F.H., T.B.), Department of Medicine, Division of Biomedical Statistics and Informatics (K.R.K.), Department of Health Sciences Research, and Division of Medical Oncology (M.P.G., J.N.I.), Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905; Division of Hematology/Oncology (P.E.G.), Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard University, Boston, Massachusetts 02114; National Cancer Institute of Canada Clinical Trials Group (L.E.S.), Kingston, Ontario, Canada K7L 3N6; and RIKEN Center for Integrative Medical Science (M.K.), Yokohama 230-0045, Japan.
authors: Krishna R
authors: KR
authors: Kalari
authors: Division of Clinical Pharmacology (M.-F.H., M.L., L.W., R.M.W.), Department of Molecular Pharmacology and Experimental Therapeutics, Division of Rheumatology (M.-F.H., T.B.), Department of Medicine, Division of Biomedical Statistics and Informatics (K.R.K.), Department of Health Sciences Research, and Division of Medical Oncology (M.P.G., J.N.I.), Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905; Division of Hematology/Oncology (P.E.G.), Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard University, Boston, Massachusetts 02114; National Cancer Institute of Canada Clinical Trials Group (L.E.S.), Kingston, Ontario, Canada K7L 3N6; and RIKEN Center for Integrative Medical Science (M.K.), Yokohama 230-0045, Japan.
authors: Paul E
authors: PE
authors: Goss
authors: Division of Clinical Pharmacology (M.-F.H., M.L., L.W., R.M.W.), Department of Molecular Pharmacology and Experimental Therapeutics, Division of Rheumatology (M.-F.H., T.B.), Department of Medicine, Division of Biomedical Statistics and Informatics (K.R.K.), Department of Health Sciences Research, and Division of Medical Oncology (M.P.G., J.N.I.), Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905; Division of Hematology/Oncology (P.E.G.), Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard University, Boston, Massachusetts 02114; National Cancer Institute of Canada Clinical Trials Group (L.E.S.), Kingston, Ontario, Canada K7L 3N6; and RIKEN Center for Integrative Medical Science (M.K.), Yokohama 230-0045, Japan.
authors: Lois E
authors: LE
authors: Shepherd
authors: Division of Clinical Pharmacology (M.-F.H., M.L., L.W., R.M.W.), Department of Molecular Pharmacology and Experimental Therapeutics, Division of Rheumatology (M.-F.H., T.B.), Department of Medicine, Division of Biomedical Statistics and Informatics (K.R.K.), Department of Health Sciences Research, and Division of Medical Oncology (M.P.G., J.N.I.), Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905; Division of Hematology/Oncology (P.E.G.), Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard University, Boston, Massachusetts 02114; National Cancer Institute of Canada Clinical Trials Group (L.E.S.), Kingston, Ontario, Canada K7L 3N6; and RIKEN Center for Integrative Medical Science (M.K.), Yokohama 230-0045, Japan.
authors: Matthew P
authors: MP
authors: Goetz
authors: Division of Clinical Pharmacology (M.-F.H., M.L., L.W., R.M.W.), Department of Molecular Pharmacology and Experimental Therapeutics, Division of Rheumatology (M.-F.H., T.B.), Department of Medicine, Division of Biomedical Statistics and Informatics (K.R.K.), Department of Health Sciences Research, and Division of Medical Oncology (M.P.G., J.N.I.), Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905; Division of Hematology/Oncology (P.E.G.), Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard University, Boston, Massachusetts 02114; National Cancer Institute of Canada Clinical Trials Group (L.E.S.), Kingston, Ontario, Canada K7L 3N6; and RIKEN Center for Integrative Medical Science (M.K.), Yokohama 230-0045, Japan.
authors: Michiaki
authors: M
authors: Kubo
authors: Division of Clinical Pharmacology (M.-F.H., M.L., L.W., R.M.W.), Department of Molecular Pharmacology and Experimental Therapeutics, Division of Rheumatology (M.-F.H., T.B.), Department of Medicine, Division of Biomedical Statistics and Informatics (K.R.K.), Department of Health Sciences Research, and Division of Medical Oncology (M.P.G., J.N.I.), Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905; Division of Hematology/Oncology (P.E.G.), Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard University, Boston, Massachusetts 02114; National Cancer Institute of Canada Clinical Trials Group (L.E.S.), Kingston, Ontario, Canada K7L 3N6; and RIKEN Center for Integrative Medical Science (M.K.), Yokohama 230-0045, Japan.
authors: James N
authors: JN
authors: Ingle
authors: Division of Clinical Pharmacology (M.-F.H., M.L., L.W., R.M.W.), Department of Molecular Pharmacology and Experimental Therapeutics, Division of Rheumatology (M.-F.H., T.B.), Department of Medicine, Division of Biomedical Statistics and Informatics (K.R.K.), Department of Health Sciences Research, and Division of Medical Oncology (M.P.G., J.N.I.), Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905; Division of Hematology/Oncology (P.E.G.), Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard University, Boston, Massachusetts 02114; National Cancer Institute of Canada Clinical Trials Group (L.E.S.), Kingston, Ontario, Canada K7L 3N6; and RIKEN Center for Integrative Medical Science (M.K.), Yokohama 230-0045, Japan.
authors: Liewei
authors: L
authors: Wang
authors: Division of Clinical Pharmacology (M.-F.H., M.L., L.W., R.M.W.), Department of Molecular Pharmacology and Experimental Therapeutics, Division of Rheumatology (M.-F.H., T.B.), Department of Medicine, Division of Biomedical Statistics and Informatics (K.R.K.), Department of Health Sciences Research, and Division of Medical Oncology (M.P.G., J.N.I.), Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905; Division of Hematology/Oncology (P.E.G.), Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard University, Boston, Massachusetts 02114; National Cancer Institute of Canada Clinical Trials Group (L.E.S.), Kingston, Ontario, Canada K7L 3N6; and RIKEN Center for Integrative Medical Science (M.K.), Yokohama 230-0045, Japan.
authors: Richard M
authors: RM
authors: Weinshilboum
mesh_terms: D002460:Cell Line; D018925:Chemokines / Q000235:genetics*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D059372:Nucleotide Motifs / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism*
chemical_list: D018925:Chemokines; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D011518:Proto-Oncogene Proteins; D020845:Selective Estrogen Receptor Modulators; C090851:TCL1A protein, human; D004958:Estradiol