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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-04-20

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

ABSTRACT

BackgroundEstrone (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.MethodsWe 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.ResultsMultiple 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.ConclusionThese 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. More... »

PAGES

189-199

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10549-017-4243-3

DOI

http://dx.doi.org/10.1007/s10549-017-4243-3

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1084984206

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28429243


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