title: Aromatase inhibitors, estrogens and musculoskeletal pain: estrogen-dependent T-cell leukemia 1A (TCL1A) gene-mediated regulation of cytokine expression.
abstract: BACKGROUND
  Arthralgias and myalgias are major side effects associated with aromatase inhibitor (AI) therapy of breast cancer. In a recent genome-wide association study, we identified SNPs - including one that created an estrogen response element near the 3' end of the T-cell leukemia 1A (TCL1A) gene - that were associated with musculoskeletal pain in women on adjuvant AI therapy for breast cancer. We also showed estrogen-dependent, SNP-modulated variation in TCL1A expression and, in preliminary experiments, showed that TCL1A could induce IL-17RA expression. In the present study, we set out to determine whether these SNPs might influence cytokine expression and effect more widely, and, if so, to explore the mechanism of TCL1A-related AI-induced side effects.
  
  
  METHODS
  The functional genomic experiments performed included determinations of TCL1A, cytokine and cytokine receptor expression in response to estrogen treatment of U2OS cells and lymphoblastoid cell lines that had been stably transfected with estrogen receptor alpha. Changes in mRNA and protein expression after gene knockdown and overexpression were also determined, as was NF-κB transcriptional activity.
  
  
  RESULTS
  Estradiol (E2) increased TCL1A expression and, in a TCL1A SNP-dependent fashion, also altered the expression of IL-17, IL-17RA, IL-12, IL-12RB2 and IL-1R2. TCL1A expression was higher in E2-treated lymphoblastoid cell lines with variant SNP genotypes, and induction of the expression of cytokine and cytokine receptor genes was mediated by TCL1A. Finally, estrogen receptor alpha blockade with ICI-182,780 in the presence of E2 resulted in greatly increased NF-κB transcriptional activity, but only in cells that carried variant SNP genotypes. These results linked variant TCL1A SNP sequences that are associated with AI-dependent musculoskeletal pain with increased E2-dependent TCL1A expression and with downstream alterations in cytokine and cytokine receptor expression as well as NF-κB transcriptional activity.
  
  
  CONCLUSIONS
  SNPs near the 3' terminus of TCL1A were associated with AI-dependent musculoskeletal pain. E2 induced SNP-dependent TCL1A expression, which in turn altered IL-17, IL-17RA, IL-12, IL-12RB2, and IL-1R2 expression as well as NF-κB transcriptional activity. These results provide a pharmacogenomic explanation for a clinically important adverse drug reaction as well as insights into a novel estrogen-dependent mechanism for the modulation of cytokine and cytokine receptor expression.
authors.affiliation: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Mohan
authors.initials: M
authors.lastname: Liu
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
authors.forename: Tim
authors.initials: T
authors.lastname: Bongartz
authors.forename: John R
authors.initials: JR
authors.lastname: Hawse
authors.forename: Svetomir N
authors.initials: SN
authors.lastname: Markovic
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Paul E
authors.initials: PE
authors.lastname: Goss
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.forename: Richard M
authors.initials: RM
authors.lastname: Weinshilboum
mesh_terms: D047072:Aromatase Inhibitors / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000235:genetics*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D055106:Genome-Wide Association Study; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics; D020381:Interleukin-17 / Q000235:genetics; D059352:Musculoskeletal Pain / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D053574:Receptors, Interleukin-1 Type II / Q000235:genetics; D053707:Receptors, Interleukin-12 / Q000235:genetics; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000378:metabolism
chemical_list: D047072:Aromatase Inhibitors; D016207:Cytokines; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C508439:IL12RB2 protein, human; C109985:IL17RA protein, human; C508592:IL1R2 protein, human; D020381:Interleukin-17; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D053574:Receptors, Interleukin-1 Type II; D053707:Receptors, Interleukin-12; D053722:Receptors, Interleukin-17; C090851:TCL1A protein, human; D018664:Interleukin-12; D004958:Estradiol