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01-07-2017 | Epidemiology

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

Authors: 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. Weinshilboum

Published in: Breast Cancer Research and Treatment | Issue 1/2017

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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Title: SLCO1B1 polymorphisms and plasma estrone conjugates in postmenopausal women with ER+ breast cancer: genome-wide association studies of the estrone pathway
Authors: 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. Weinshilboum
Publication date: 01-07-2017
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2017
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-017-4243-3

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Abstract

Background

Methods

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Conclusion

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