SLCO1B1 polymorphisms and plasma estrone conjugates in postmenopausal women with ER+ breast cancer: genome-wide association studies of the estrone pathway

Tanda M. Dudenkov, James N. Ingle, Aman U. Buzdar, Mark E. Robson, Michiaki Kubo, Irada Ibrahim-zada, Anthony Batzler, Gregory D. Jenkins, Tracy L. Pietrzak, Erin E. Carlson, Poulami Barman, Matthew Philip Goetz, Donald W Northfelt, Alvaro Moreno-Aspita, Clark V. Williard, Krishna R Kalari, Yusuke Nakamura, Liewei M Wang, Richard M Weinshilboum

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: Estrone (E1), the major circulating estrogen in postmenopausal women, promotes estrogen-receptor positive (ER+) breast tumor growth and proliferation. Two major reactions contribute to E1 plasma concentrations, aromatase (CYP19A1) catalyzed E1 synthesis from androstenedione and steroid sulfatase (STS) catalyzed hydrolysis of estrone conjugates (E1Cs). E1Cs have been associated with breast cancer risk and may contribute to tumor progression since STS is expressed in breast cancer where its activity exceeds that of aromatase. Methods: We performed genome-wide association studies (GWAS) to identify SNPs associated with variation in plasma concentrations of E1Cs, E1, and androstenedione in 774 postmenopausal women with resected early-stage ER+ breast cancer. Hormone concentrations were measured prior to aromatase inhibitor therapy. Results: Multiple SNPs in SLCO1B1, a gene encoding a hepatic influx transporter, displayed genome-wide significant associations with E1C plasma concentrations and with the E1C/E1 ratio. The top SNP for E1C concentrations, rs4149056 (p = 3.74E−11), was a missense variant that results in reduced transporter activity. Patients homozygous for the variant allele had significantly higher average E1C plasma concentrations than did other patients. Furthermore, three other SLCO1B1 SNPs, not in LD with rs4149056, were associated with both E1C concentrations and the E1C/E1 ratio and were cis-eQTLs for SLCO1B3. GWAS signals of suggestive significance were also observed for E1, androstenedione, and the E1/androstenedione ratio. Conclusion: These results suggest a mechanism for genetic variation in E1C plasma concentrations as well as possible SNP biomarkers to identify ER+ breast cancer patients for whom STS inhibitors might be of clinical value.

Original languageEnglish (US)
Pages (from-to)189-199
Number of pages11
JournalBreast Cancer Research and Treatment
Volume164
Issue number1
DOIs
StatePublished - Jul 1 2017

Fingerprint

Estrone
Genome-Wide Association Study
Androstenedione
Single Nucleotide Polymorphism
Steryl-Sulfatase
Breast Neoplasms
Aromatase
Aromatase Inhibitors
Estrogen Receptors
Estrogens
Hydrolysis
Biomarkers
Alleles
Genome
Hormones
Liver
Growth
Genes
Neoplasms

Keywords

  • Breast cancer
  • Estrone conjugates
  • Genome-wide association studies
  • SLCO1B1
  • SLCO1B3
  • Steroid sulfatase inhibitors

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

SLCO1B1 polymorphisms and plasma estrone conjugates in postmenopausal women with ER+ breast cancer : genome-wide association studies of the estrone pathway. / Dudenkov, Tanda M.; Ingle, James N.; Buzdar, Aman U.; Robson, Mark E.; Kubo, Michiaki; Ibrahim-zada, Irada; Batzler, Anthony; Jenkins, Gregory D.; Pietrzak, Tracy L.; Carlson, Erin E.; Barman, Poulami; Goetz, Matthew Philip; Northfelt, Donald W; Moreno-Aspita, Alvaro; Williard, Clark V.; Kalari, Krishna R; Nakamura, Yusuke; Wang, Liewei M; Weinshilboum, Richard M.

In: Breast Cancer Research and Treatment, Vol. 164, No. 1, 01.07.2017, p. 189-199.

Research output: Contribution to journalArticle

Dudenkov, TM, Ingle, JN, Buzdar, AU, Robson, ME, Kubo, M, Ibrahim-zada, I, Batzler, A, Jenkins, GD, Pietrzak, TL, Carlson, EE, Barman, P, Goetz, MP, Northfelt, DW, Moreno-Aspita, A, Williard, CV, Kalari, KR, Nakamura, Y, Wang, LM & Weinshilboum, RM 2017, 'SLCO1B1 polymorphisms and plasma estrone conjugates in postmenopausal women with ER+ breast cancer: genome-wide association studies of the estrone pathway', Breast Cancer Research and Treatment, vol. 164, no. 1, pp. 189-199. https://doi.org/10.1007/s10549-017-4243-3
Dudenkov, Tanda M. ; Ingle, James N. ; Buzdar, Aman U. ; Robson, Mark E. ; Kubo, Michiaki ; Ibrahim-zada, Irada ; Batzler, Anthony ; Jenkins, Gregory D. ; Pietrzak, Tracy L. ; Carlson, Erin E. ; Barman, Poulami ; Goetz, Matthew Philip ; Northfelt, Donald W ; Moreno-Aspita, Alvaro ; Williard, Clark V. ; Kalari, Krishna R ; Nakamura, Yusuke ; Wang, Liewei M ; Weinshilboum, Richard M. / SLCO1B1 polymorphisms and plasma estrone conjugates in postmenopausal women with ER+ breast cancer : genome-wide association studies of the estrone pathway. In: Breast Cancer Research and Treatment. 2017 ; Vol. 164, No. 1. pp. 189-199.
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abstract = "Background: Estrone (E1), the major circulating estrogen in postmenopausal women, promotes estrogen-receptor positive (ER+) breast tumor growth and proliferation. Two major reactions contribute to E1 plasma concentrations, aromatase (CYP19A1) catalyzed E1 synthesis from androstenedione and steroid sulfatase (STS) catalyzed hydrolysis of estrone conjugates (E1Cs). E1Cs have been associated with breast cancer risk and may contribute to tumor progression since STS is expressed in breast cancer where its activity exceeds that of aromatase. Methods: We performed genome-wide association studies (GWAS) to identify SNPs associated with variation in plasma concentrations of E1Cs, E1, and androstenedione in 774 postmenopausal women with resected early-stage ER+ breast cancer. Hormone concentrations were measured prior to aromatase inhibitor therapy. Results: Multiple SNPs in SLCO1B1, a gene encoding a hepatic influx transporter, displayed genome-wide significant associations with E1C plasma concentrations and with the E1C/E1 ratio. The top SNP for E1C concentrations, rs4149056 (p = 3.74E−11), was a missense variant that results in reduced transporter activity. Patients homozygous for the variant allele had significantly higher average E1C plasma concentrations than did other patients. Furthermore, three other SLCO1B1 SNPs, not in LD with rs4149056, were associated with both E1C concentrations and the E1C/E1 ratio and were cis-eQTLs for SLCO1B3. GWAS signals of suggestive significance were also observed for E1, androstenedione, and the E1/androstenedione ratio. Conclusion: These results suggest a mechanism for genetic variation in E1C plasma concentrations as well as possible SNP biomarkers to identify ER+ breast cancer patients for whom STS inhibitors might be of clinical value.",
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T1 - SLCO1B1 polymorphisms and plasma estrone conjugates in postmenopausal women with ER+ breast cancer

T2 - genome-wide association studies of the estrone pathway

AU - Dudenkov, Tanda M.

AU - Ingle, James N.

AU - Buzdar, Aman U.

AU - Robson, Mark E.

AU - Kubo, Michiaki

AU - Ibrahim-zada, Irada

AU - Batzler, Anthony

AU - Jenkins, Gregory D.

AU - Pietrzak, Tracy L.

AU - Carlson, Erin E.

AU - Barman, Poulami

AU - Goetz, Matthew Philip

AU - Northfelt, Donald W

AU - Moreno-Aspita, Alvaro

AU - Williard, Clark V.

AU - Kalari, Krishna R

AU - Nakamura, Yusuke

AU - Wang, Liewei M

AU - Weinshilboum, Richard M

PY - 2017/7/1

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N2 - Background: Estrone (E1), the major circulating estrogen in postmenopausal women, promotes estrogen-receptor positive (ER+) breast tumor growth and proliferation. Two major reactions contribute to E1 plasma concentrations, aromatase (CYP19A1) catalyzed E1 synthesis from androstenedione and steroid sulfatase (STS) catalyzed hydrolysis of estrone conjugates (E1Cs). E1Cs have been associated with breast cancer risk and may contribute to tumor progression since STS is expressed in breast cancer where its activity exceeds that of aromatase. Methods: We performed genome-wide association studies (GWAS) to identify SNPs associated with variation in plasma concentrations of E1Cs, E1, and androstenedione in 774 postmenopausal women with resected early-stage ER+ breast cancer. Hormone concentrations were measured prior to aromatase inhibitor therapy. Results: Multiple SNPs in SLCO1B1, a gene encoding a hepatic influx transporter, displayed genome-wide significant associations with E1C plasma concentrations and with the E1C/E1 ratio. The top SNP for E1C concentrations, rs4149056 (p = 3.74E−11), was a missense variant that results in reduced transporter activity. Patients homozygous for the variant allele had significantly higher average E1C plasma concentrations than did other patients. Furthermore, three other SLCO1B1 SNPs, not in LD with rs4149056, were associated with both E1C concentrations and the E1C/E1 ratio and were cis-eQTLs for SLCO1B3. GWAS signals of suggestive significance were also observed for E1, androstenedione, and the E1/androstenedione ratio. Conclusion: These results suggest a mechanism for genetic variation in E1C plasma concentrations as well as possible SNP biomarkers to identify ER+ breast cancer patients for whom STS inhibitors might be of clinical value.

AB - Background: Estrone (E1), the major circulating estrogen in postmenopausal women, promotes estrogen-receptor positive (ER+) breast tumor growth and proliferation. Two major reactions contribute to E1 plasma concentrations, aromatase (CYP19A1) catalyzed E1 synthesis from androstenedione and steroid sulfatase (STS) catalyzed hydrolysis of estrone conjugates (E1Cs). E1Cs have been associated with breast cancer risk and may contribute to tumor progression since STS is expressed in breast cancer where its activity exceeds that of aromatase. Methods: We performed genome-wide association studies (GWAS) to identify SNPs associated with variation in plasma concentrations of E1Cs, E1, and androstenedione in 774 postmenopausal women with resected early-stage ER+ breast cancer. Hormone concentrations were measured prior to aromatase inhibitor therapy. Results: Multiple SNPs in SLCO1B1, a gene encoding a hepatic influx transporter, displayed genome-wide significant associations with E1C plasma concentrations and with the E1C/E1 ratio. The top SNP for E1C concentrations, rs4149056 (p = 3.74E−11), was a missense variant that results in reduced transporter activity. Patients homozygous for the variant allele had significantly higher average E1C plasma concentrations than did other patients. Furthermore, three other SLCO1B1 SNPs, not in LD with rs4149056, were associated with both E1C concentrations and the E1C/E1 ratio and were cis-eQTLs for SLCO1B3. GWAS signals of suggestive significance were also observed for E1, androstenedione, and the E1/androstenedione ratio. Conclusion: These results suggest a mechanism for genetic variation in E1C plasma concentrations as well as possible SNP biomarkers to identify ER+ breast cancer patients for whom STS inhibitors might be of clinical value.

KW - Breast cancer

KW - Estrone conjugates

KW - Genome-wide association studies

KW - SLCO1B1

KW - SLCO1B3

KW - Steroid sulfatase inhibitors

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