Estrogen, SNP-dependent chemokine expression and selective estrogen receptor modulator regulation

Ming Fen Ho, Tim Bongartz, Mohan Liu, Krishna R. Kalari, Paul E. Goss, Lois E. Shepherd, Matthew P. Goetz, Michiaki Kubo, James N. Ingle, Liewei Wang, Richard M. Weinshilboum

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

We previously reported, on the basis of a genome-wide association study for aromatase inhibitorinduced 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.

Original languageEnglish (US)
Pages (from-to)382-398
Number of pages17
JournalMolecular Endocrinology
Volume30
Issue number3
DOIs
StatePublished - Mar 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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