SLCO1B1 polymorphisms and plasma estrone conjugates in postmenopausal women with ER+ breast cancer: genome-wide association studies of the estrone pathway
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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.
KeywordsEstrone 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, ClinicalTrials.gov study number NCT00283608. Tanda Dudenkov was supported by the National Institute of General Medical Sciences (T32 GM 65841).
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Conflict of interest
The authors declare no potential conflicts of interest.
- 4.Kohler BA, Sherman RL, Howlader N, Jemal A, Ryerson AB, Henry KA et al (2015) Annual report to the nation on the status of cancer, 1975-2011, featuring incidence of breast cancer subtypes by race/ethnicity, poverty, and state. J Natl Cancer Inst. doi: 10.1093/jnci/djv048 PubMedPubMedCentralGoogle Scholar
- 9.Vermeulen A, Deslypere JP, Paridaens R, Leclercq G, Roy F, Heuson JC (1986) Aromatase, 17 beta-hydroxysteroid dehydrogenase and intratissular sex hormone concentrations in cancerous and normal glandular breast tissue in postmenopausal women. Eur J Cancer Clin Oncol 22(4):515–525CrossRefPubMedGoogle Scholar
- 10.Pasqualini JR, Chetrite G, Blacker C, Feinstein MC, Delalonde L, Talbi M, Maloche C (1996) Concentrations of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients. J Clin Endocrinol Metab 81(4):1460–1464PubMedGoogle Scholar
- 12.Raftogianis R, Creveling C, Weinshilboum R, Weisz J (2000) Estrogen metabolism by conjugation. J Natl Cancer Inst Monogr 27(113):24Google Scholar
- 13.Iwamori, M. (2005). Estrogen Sulfatase. B.-M.(ed). in Enzymology, (Academic Press), pp. 293–302Google Scholar
- 28.Beckmann L, Husing A, Setiawan VW, Amiano P, Clavel-Chapelon F, Chanock SJ et al (2011) Comprehensive analysis of hormone and genetic variation in 36 genes related to steroid hormone metabolism in pre- and postmenopausal women from the breast and prostate cancer cohort consortium [BPC3]. J Clin Endocrinol Metab 96(2):E360–E367CrossRefPubMedGoogle Scholar
- 45.Lee E, Schumacher F, Lewinger JP, Neuhausen SL, Anton-Culver H, Horn-Ross PL et al (2011) The association of polymorphisms in hormone metabolism pathway genes, menopausal hormone therapy, and breast cancer risk: a nested case-control study in the California teachers study cohort. Breast Cancer Res 13(2):R37CrossRefPubMedPubMedCentralGoogle Scholar