Aromatase inhibitors, estrogens and musculoskeletal pain

Estrogen-dependent T-cell leukemia 1A (TCL1A) gene-mediated regulation of cytokine expression

Mohan Liu, Liewei Wang, Tim Bongartz, John R. Hawse, Svetomir N. Markovic, Daniel J. Schaid, Taisei Mushiroda, Michiaki Kubo, Yusuke Nakamura, Naoyuki Kamatani, Paul E. Goss, James N. Ingle, Richard M. Weinshilboum

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Abstract

Introduction: 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.

Original languageEnglish
Article numberR41
JournalBreast Cancer Research
Volume14
Issue number2
DOIs
Publication statusPublished - 09-03-2012

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T-Cell Leukemia
Musculoskeletal Pain
Aromatase Inhibitors
Estrogens
Cytokines
Single Nucleotide Polymorphism
Genes
Cytokine Receptors
Interleukin-17
Estrogen Receptor alpha
Interleukin-12
Genotype
Breast Neoplasms
Gene Knockdown Techniques
Cell Line
Genome-Wide Association Study
Pharmacogenetics
Myalgia
Arthralgia
Response Elements

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Liu, Mohan ; Wang, Liewei ; Bongartz, Tim ; Hawse, John R. ; Markovic, Svetomir N. ; Schaid, Daniel J. ; Mushiroda, Taisei ; Kubo, Michiaki ; Nakamura, Yusuke ; Kamatani, Naoyuki ; Goss, Paul E. ; Ingle, James N. ; Weinshilboum, Richard M. / Aromatase inhibitors, estrogens and musculoskeletal pain : Estrogen-dependent T-cell leukemia 1A (TCL1A) gene-mediated regulation of cytokine expression. In: Breast Cancer Research. 2012 ; Vol. 14, No. 2.
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title = "Aromatase inhibitors, estrogens and musculoskeletal pain: Estrogen-dependent T-cell leukemia 1A (TCL1A) gene-mediated regulation of cytokine expression",
abstract = "Introduction: 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.",
author = "Mohan Liu and Liewei Wang and Tim Bongartz and Hawse, {John R.} and Markovic, {Svetomir N.} and Schaid, {Daniel J.} and Taisei Mushiroda and Michiaki Kubo and Yusuke Nakamura and Naoyuki Kamatani and Goss, {Paul E.} and Ingle, {James N.} and Weinshilboum, {Richard M.}",
year = "2012",
month = "3",
day = "9",
doi = "10.1186/bcr3137",
language = "English",
volume = "14",
journal = "Breast Cancer Research",
issn = "1465-5411",
publisher = "BioMed Central",
number = "2",

}

Liu, M, Wang, L, Bongartz, T, Hawse, JR, Markovic, SN, Schaid, DJ, Mushiroda, T, Kubo, M, Nakamura, Y, Kamatani, N, Goss, PE, Ingle, JN & Weinshilboum, RM 2012, 'Aromatase inhibitors, estrogens and musculoskeletal pain: Estrogen-dependent T-cell leukemia 1A (TCL1A) gene-mediated regulation of cytokine expression', Breast Cancer Research, vol. 14, no. 2, R41. https://doi.org/10.1186/bcr3137

Aromatase inhibitors, estrogens and musculoskeletal pain : Estrogen-dependent T-cell leukemia 1A (TCL1A) gene-mediated regulation of cytokine expression. / Liu, Mohan; Wang, Liewei; Bongartz, Tim; Hawse, John R.; Markovic, Svetomir N.; Schaid, Daniel J.; Mushiroda, Taisei; Kubo, Michiaki; Nakamura, Yusuke; Kamatani, Naoyuki; Goss, Paul E.; Ingle, James N.; Weinshilboum, Richard M.

In: Breast Cancer Research, Vol. 14, No. 2, R41, 09.03.2012.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Aromatase inhibitors, estrogens and musculoskeletal pain

T2 - Estrogen-dependent T-cell leukemia 1A (TCL1A) gene-mediated regulation of cytokine expression

AU - Liu, Mohan

AU - Wang, Liewei

AU - Bongartz, Tim

AU - Hawse, John R.

AU - Markovic, Svetomir N.

AU - Schaid, Daniel J.

AU - Mushiroda, Taisei

AU - Kubo, Michiaki

AU - Nakamura, Yusuke

AU - Kamatani, Naoyuki

AU - Goss, Paul E.

AU - Ingle, James N.

AU - Weinshilboum, Richard M.

PY - 2012/3/9

Y1 - 2012/3/9

N2 - Introduction: 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.

AB - Introduction: 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.

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