TCL1A Single-Nucleotide Polymorphisms and Estrogen-Mediated Toll-Like Receptor-MyD88–Dependent Nuclear Factor-kB Activation: Single-Nucleotide Polymorphism– and Selective Estrogen Receptor Modulator–Dependent Modification of Inflammation and Immune Response

Ming Fen Ho, James N. Ingle, Tim Bongartz, Krishna R. Kalari, Paul E. Goss, Lois E. Shepherd, Taisei Mushiroda, Michiaki Kubo, Liewei Wang, Richard M. Weinshilboum

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

In a previous genome-wide association study (GWAS) for musculoskeletal adverse events during aromatase inhibitor therapy for breast cancer, we reported that single nucleotide polymorphisms (SNPs) near the TCL1A gene were associated with this adverse drug reaction. Functional genomic studies showed that TCL1A expression was induced by estradiol, but only in cells with the variant sequence for the top GWAS SNP (rs11849538), a SNP that created a functional estrogen response element. In addition, TCL1A genotype influenced the downstream expression of a series of cytokines and chemokines and had a striking effect on nuclear factor kB (NF-kB) transcriptional activity. Furthermore, this SNP-dependent regulation could be reversed by selective ER modulators (SERMs). The present study was designed to pursue mechanisms underlying TCL1A SNP-mediated, estrogen-dependent NF-kB activation. Functional genomic studies were performed using a panel of 300 lymphoblastoid cell lines for which we had generated genome-wide SNP and gene expression data. It is known that toll-like receptors (TLRs) can regulate NF-kB signaling by a process that requires the adaptor protein MyD88. We found that TLR2, TLR7, TLR9, and TLR10 expression, as well as that of MyD88, could be modulated by TCL1A in a SNP and estrogen-dependent fashion and that these effects were reversed in the presence of SERMs. Furthermore, MyD88 inhibition blocked the TCL1A SNP and estrogen-dependent NF-kB activation, as well as protein-protein interaction between TCL1A and MyD88. These observations greatly expand the range of pathways influenced by TCL1A genotype and raise the possibility that this estrogen- and SNP-dependent regulation might be altered pharmacologically by SERMs.

Original languageEnglish
Pages (from-to)175-184
Number of pages10
JournalMolecular Pharmacology
Volume92
Issue number2
DOIs
Publication statusPublished - 08-2017

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Fingerprint Dive into the research topics of 'TCL1A Single-Nucleotide Polymorphisms and Estrogen-Mediated Toll-Like Receptor-MyD88–Dependent Nuclear Factor-kB Activation: Single-Nucleotide Polymorphism– and Selective Estrogen Receptor Modulator–Dependent Modification of Inflammation and Immune Response'. Together they form a unique fingerprint.

  • Cite this