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. 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

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Free PMC article

SLCO1B1 Polymorphisms and Plasma Estrone Conjugates in Postmenopausal Women With ER+ Breast Cancer: Genome-Wide Association Studies of the Estrone Pathway

Tanda M Dudenkov et al. Breast Cancer Res Treat. .
Free PMC article

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.

Conflict of interest statement

Compliance with ethical standards

Conflict of interest The authors declare no potential conflicts of interest.

Figures

Fig. 1
Fig. 1
Manhattan plots showing GWAS results for plasma concentrations of (A). Estrone Conjugates (E1C), (B). the ratio of E1C/E1, (C). Estrone (E1) in 774 postmenopausal women with ER+ breast cancer prior to the initiation of endocrine therapy. Dashed lines represent thresholds for genome-wide significance (p ≤ 5.0E–08, green) and suggestive significance (p ≤ 5.0E–06, gray)
Fig. 2
Fig. 2
Regional plots of the genome-wide significant SNP signal across SLCO1B1 from (A). GWAS of E1C which shows the top SNP, rs4149056 (blue arrow), a missense variant that results in a plasma membrane transporter with reduced activity, (B) GWAS of E1C/E1 which shows the top SNP, rs10841753 (purple point), which is an intronic variant that is in high LD (R2 = 1.00, CEU population, distance = 8443 bp), with another missense variant, rs11045819 (red arrow) in populations of European descent, but it is a signal independent from rs4149056 (R2 = 0.013, CEU population, distance = 101179 bp). The black arrow highlights 3 SNPs (rs11045828, rs10841755, and rs11045834) that are cis-eQTLs for SLCO1B3 and are associated with breast cancer risk
Fig. 3
Fig. 3
Mean plasma E1C concentrations for each genotype of rs4149056 (with 95% confidence intervals shown) in postmenopausal women with ER+ breast cancer. Red points with red horizontal bars indicate the mean values for each genotype

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