Breast Cancer Research and Treatment

, Volume 164, Issue 1, pp 189–199 | Cite as

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 P. Goetz
  • Donald W. Northfelt
  • Alvaro Moreno-Aspita
  • Clark V. Williard
  • Krishna R. Kalari
  • Yusuke Nakamura
  • Liewei Wang
  • Richard M. WeinshilboumEmail author



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.


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.


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.


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.


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



This work was supported, in part, by National Institutes of Health Grants U19 GM61388 (The Pharmacogenomics Research Network), R01 GM28157, U01 HG005137, R01 CA138461, R01 CA133049, and P50 CA166201 (Mayo Clinic Breast Cancer Specialized Program of Research Excellence), The RIKEN Center for Integrative Medical Sciences, the Biobank Japan Project funded by the Ministry of Education, Culture, Sports, Science and Technology (Japan), and a generous gift from the Prospect Creek Foundation, study number NCT00283608. Tanda Dudenkov was supported by the National Institute of General Medical Sciences (T32 GM 65841).

Compliance with ethical standards

Conflict of interest

The authors declare no potential conflicts of interest.

Supplementary material

10549_2017_4243_MOESM1_ESM.doc (978 kb)
Supplementary material 1 (DOC 978 kb)


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Tanda M. Dudenkov
    • 1
  • James N. Ingle
    • 2
  • Aman U. Buzdar
    • 3
  • Mark E. Robson
    • 4
  • Michiaki Kubo
    • 5
  • Irada Ibrahim-zada
    • 1
    • 6
  • Anthony Batzler
    • 7
  • Gregory D. Jenkins
    • 7
  • Tracy L. Pietrzak
    • 8
  • Erin E. Carlson
    • 7
  • Poulami Barman
    • 7
  • Matthew P. Goetz
    • 2
  • Donald W. Northfelt
    • 9
  • Alvaro Moreno-Aspita
    • 10
  • Clark V. Williard
    • 11
  • Krishna R. Kalari
    • 7
  • Yusuke Nakamura
    • 12
  • Liewei Wang
    • 1
  • Richard M. Weinshilboum
    • 1
    Email author
  1. 1.Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental TherapeuticsMayo ClinicRochesterUSA
  2. 2.Division of Medical Oncology, Department of OncologyMayo ClinicRochesterUSA
  3. 3.Department of Breast OncologyM.D. Anderson Cancer CenterHoustonUSA
  4. 4.Breast Medicine ServiceMemorial Sloan Kettering Cancer CenterNew YorkUSA
  5. 5.RIKEN Center for Integrative Medical SciencesYokohama CityJapan
  6. 6.University of ColoradoDenverUSA
  7. 7.Department of Health Sciences ResearchMayo ClinicRochesterUSA
  8. 8.Information TechnologyMayo ClinicRochesterUSA
  9. 9.Division of Hematology/OncologyMayo ClinicScottsdaleUSA
  10. 10.Division of Hematology/OncologyMayo ClinicJacksonvilleUSA
  11. 11.inVentiv HealthPrincetonUSA
  12. 12.Department of Medicine, School of MedicineUniversity of ChicagoChicagoUSA

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