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Breast Cancer Res Treat. 2017 Jul;164(1):189-199. doi: 10.1007/s10549-017-4243-3. Epub 2017 Apr 20.

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

Author information

1
Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
2
Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, MN, USA.
3
Department of Breast Oncology, M.D. Anderson Cancer Center, Houston, TX, USA.
4
Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
5
RIKEN Center for Integrative Medical Sciences, Yokohama City, Japan.
6
University of Colorado, Denver, USA.
7
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
8
Information Technology, Mayo Clinic, Rochester, MN, USA.
9
Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA.
10
Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA.
11
inVentiv Health, Princeton, NJ, USA.
12
Department of Medicine, School of Medicine, University of Chicago, Chicago, IL, USA.
13
Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA. weinshilboum.richard@mayo.edu.

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.

KEYWORDS:

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

PMID:
28429243
PMCID:
PMC5600471
DOI:
10.1007/s10549-017-4243-3
[Indexed for MEDLINE]
Free PMC Article

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