nach oben

Erschienen in:

20.04.2017 | Epidemiology

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

verfasst von: 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

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 1/2017

Einloggen, um Zugang zu erhalten

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.

Nur mit Berechtigung zugänglich

Silberstein GB, Van Horn K, Shyamala G, Daniel CW (1994) Essential role of endogenous estrogen in directly stimulating mammary growth demonstrated by implants containing pure antiestrogens. Endocrinology 134(1):84–90CrossRefPubMed

Laidlaw IJ, Clarke RB, Howell A, Owen AW, Potten CS, Anderson E (1995) The proliferation of normal human breast tissue implanted into athymic nude mice is stimulated by estrogen but not progesterone. Endocrinology 136(1):164–171CrossRefPubMed

Hurd C, Khattree N, Dinda S, Alban P, Moudgil VK (1997) Regulation of tumor suppressor proteins, p53 and retinoblastoma, by estrogen and antiestrogens in breast cancer cells. Oncogene 15(8):991–995CrossRefPubMed

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 PubMedPubMedCentral

Rich RL, Hoth LR, Geoghegan KF, Brown TA, LeMotte PK, Simons SP, Hensley P, Myszka DG (2002) Kinetic analysis of estrogen receptor/ligand interactions. Proc Natl Acad Sci 99:8562–8567CrossRefPubMedPubMedCentral

Pasqualini JR, Gelly C, Nguyen BL, Vella C (1989) Importance of estrogen sulfates in breast cancer. J Steroid Biochem Mol Biol 34(1-6):155–163CrossRef

Ruder HJ, Loriaux L, Lipsett MB (1972) Estrone sulfate: production rate and metabolism in man. J Clin Investig 51(4):1020–1033CrossRefPubMedPubMedCentral

Noel CT, Reed MJ, Jacobs HS, James VH (1981) The plasma concentration of oestrone sulphate in postmenopausal women: lack of diurnal variation, effect of ovariectomy, age and weight. J Steroid Biochem Mol Biol 14(11):1101–1105CrossRef

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):515–525CrossRefPubMed

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):1460–1464PubMed

11.

Roberts KD, Rochefort JG, Bleau G, Chapdelaine A (1980) Plasma estrone sulfate levels in postmenopausal women. Steroids 35:179–187CrossRefPubMed

12.

Raftogianis R, Creveling C, Weinshilboum R, Weisz J (2000) Estrogen metabolism by conjugation. J Natl Cancer Inst Monogr 27(113):24

13.

Iwamori, M. (2005). Estrogen Sulfatase. B.-M.(ed). in Enzymology, (Academic Press), pp. 293–302

14.

Key T, Appleby P, Barnes I, Reeves G, Endogenous H, Breast Cancer Collaborative Group (2002) Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 94(8):606–616CrossRefPubMed

15.

Missmer SA, Eliassen AH, Barbieri RL, Hankinson SE (2004) Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women. J Natl Cancer Inst 96(24):1856–1865CrossRefPubMed

16.

Tworoger SS, Rosner BA, Willett WC, Hankinson SE (2011) The combined influence of multiple sex and growth hormones on risk of postmenopausal breast cancer: a nested case-control study. Breast Cancer Res 13(5):R99CrossRefPubMedPubMedCentral

17.

Miyoshi Y, Tanji Y, Taguchi T, Tamaki Y, Noguchi S (2003) Association of serum estrone levels with estrogen receptor-positive breast cancer risk in postmenopausal Japanese women. Clin Cancer Res 9(6):2229–2233PubMed

18.

Kaaks R, Rinaldi S, Key TJ, Berrino F, Peeters PHM, Biessy C et al (2005) Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. Endocr Relat Cancer 12(4):1071–1082CrossRefPubMed

19.

Bonney RC, Reed MJ, Davidson K, Beranek PA, James VH (1983) The relationship between 17 beta-hydroxysteroid dehydrogenase activity and oestrogen concentrations in human breast tumours and in normal breast tissue. Clin Endocrinol 19(6):727–739CrossRef

20.

Honma N, Saji S, Hirose M, Horiguchi S, Kuroi K, Hayashi S et al (2011) Sex steroid hormones in pairs of tumor and serum from breast cancer patients and pathobiological role of androstene-3beta, 17beta-diol. Cancer Sci 102(10):1848–1854CrossRefPubMed

21.

Dowsett M, Forbes JF, Bradley R, Ingle J, Aihara T, Bliss J et al (2015) Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet 386(10001):1341–1352CrossRefPubMed

22.

Purohit A, Woo LW, Singh A, Winterborn CJ, Potter BV, Reed MJ (1996) In vivo activity of 4-methylcoumarin-7-O-sulfamate, a nonsteroidal, nonestrogenic steroid sulfatase inhibitor. Cancer Res 56(21):4950–4955PubMed

23.

Stanway SJ, Purohit A, Woo LW, Sufi S, Vigushin D, Ward R et al (2006) Phase I study of STX 64 [667 Coumate] in breast cancer patients: the first study of a steroid sulfatase inhibitor. Clin Cancer Res 12(5):1585–1592CrossRefPubMed

24.

Ishida H, Nakata T, Suzuki M, Shiotsu Y, Tanaka H, Sato N et al (2007) A novel steroidal selective steroid sulfatase inhibitor KW-2581 inhibits sulfated-estrogen dependent growth of breast cancer cells in vitro and in animal models. Breast Cancer Res Treat 106(2):215–227CrossRefPubMed

25.

Palmieri C, Januszewski A, Stanway S, Coombes RC (2011) Irosustat: a first-generation steroid sulfatase inhibitor in breast cancer. Expert Rev Anticancer Ther 11(2):179–183CrossRefPubMed

26.

Dunning AM, Dowsett M, Healey CS, Tee L, Luben RN, Folkerd E et al (2004) Polymorphisms associated with circulating sex hormone levels in postmenopausal women. J Natl Cancer Inst 96(12):936–945CrossRefPubMed

27.

Haiman CA, Dossus L, Setiawan VW, Stram DO, Dunning AM, Thomas G et al (2007) Genetic variation at the CYP19A1 locus predicts circulating estrogen levels but not breast cancer risk in postmenopausal women. Cancer Res 67(5):1893–1897CrossRefPubMed

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–E367CrossRefPubMed

29.

Liu M, Ingle JN, Fridley BL, Buzdar AU, Robson ME, Kubo M et al (2013) TSPYL5 SNPs: association with plasma estradiol concentrations and aromatase expression. Mol Endocrinol 27(4):657–670CrossRefPubMedPubMedCentral

30.

Prescott J, Thompson DJ, Kraft P, Chanock SJ, Audley T, Brown J et al (2012) Genome-wide association study of circulating estradiol, testosterone, and sex hormone-binding globulin in postmenopausal women. PLoS One 7(6):e37815CrossRefPubMedPubMedCentral

31.

Ingle JN, Buzdar AU, Schaid DJ, Goetz MP, Batzler A, Robson ME et al (2010) Variation in anastrozole metabolism and pharmacodynamics in women with early breast cancer. Cancer Res 70(8):3278–3286CrossRefPubMedPubMedCentral

32.

Ingle JN, Kalari KR, Buzdar AU, Robson ME, Goetz MP, Desta Z et al (2015) Estrogens and their precursors in postmenopausal women with early breast cancer receiving anastrozole. Steroids 99:32–38. doi:10.1016/j.steroids.2014.08.007 CrossRefPubMed

33.

Browning SR, Browning BL (2007) Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. Am J Hum Genet 81(5):1084–1097CrossRefPubMedPubMedCentral

34.

Van der Waerden BL (1952) Order tests for the two-sample problem and their power. Indag Math 14:453–458CrossRef

35.

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575CrossRefPubMedPubMedCentral

36.

Tirona RG, Leake BF, Merino G, Kim RB (2001) Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J Biol Chem 276(38):35669–35675CrossRefPubMed

37.

Obaidat A, Roth M, Hagenbuch B (2012) The expression and function of organic anion transporting polypeptides in normal tissues and in cancer. Annu Rev Pharmacol Toxicol 52:135–151CrossRefPubMed

38.

Genomes Project (2015) A global reference for human genetic variation. Nature 526(7571):68–74CrossRef

39.

The GTEx Consortium (2015) Human genomics. The genotype-tissue expression [GTEx] pilot analysis: multitissue gene regulation in humans. Science 348(6235):648–660CrossRef

40.

Search Collaborative Group (2008) SLCO1B1 variants and statin-induced myopathy–a genomewide study. N Engl J Med 359(8):789–799CrossRef

41.

Johnson AD, Kavousi M, Smith AV, Chen MH, Dehghan A, Aspelund T et al (2009) Genome-wide association meta-analysis for total serum bilirubin levels. Hum Mol Genet 18(14):2700–2710CrossRefPubMedPubMedCentral

42.

Coviello AD, Haring R, Wellons M, Vaidya D, Lehtimaki T, Keildson S et al (2012) A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation. Plos Genet 8(7):e1002805CrossRefPubMedPubMedCentral

43.

Shin SY, Fauman EB, Petersen AK, Krumsiek J, Santos R, Huang J et al (2014) An atlas of genetic influences on human blood metabolites. Nat Genet 46(6):543–550CrossRefPubMedPubMedCentral

44.

Gui C, Miao Y, Thompson L, Wahlgren B, Mock M, Stieger B, Hagenbuch B (2008) Effect of pregnane X receptor ligands on transport mediated by human OATP1B1 and OATP1B3. Eur J Pharmacol 584(1):57–65CrossRefPubMedPubMedCentral

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):R37CrossRefPubMedPubMedCentral

46.

Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E et al (2012) The cbio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2:401–404CrossRefPubMed

47.

Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E et al (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cbioportal. Sci Signal 6(269):l1CrossRef

48.

Nozawa T, Suzuki M, Takahashi K, Yabuuchi H, Maeda T, Tsuji A, Tamai I (2004) Involvement of estrone-3-sulfate transporters in proliferation of hormone-dependent breast cancer cells. J Pharmacol Exp Ther 311(3):1032–1037CrossRefPubMed

49.

Banerjee N, Allen C, Bendayan R (2012) Differential role of organic anion-transporting polypeptides in estrone-3-sulphate uptake by breast epithelial cells and breast cancer cells. J Pharmacol Exp Ther 342(2):510–519CrossRefPubMed

50.

Higuchi T, Endo M, Hanamura T, Gohno T, Niwa T, Yamaguchi Y et al (2016) Contribution of estrone Sulfate to cell proliferation in aromatase inhibitor (AI) –resistant, hormone receptor-positive breast cancer. PLoS One 11(5):e0155844CrossRefPubMedPubMedCentral

51.

Utsumi T, Yoshimura N, Takeuchi S, Ando J, Maruta M, Maeda K, Harada N (1999) Steroid sulfatase expression is an independent predictor of recurrence in human breast cancer. Cancer Res 59(2):377–381PubMed

Titel: SLCO1B1 polymorphisms and plasma estrone conjugates in postmenopausal women with ER+ breast cancer: genome-wide association studies of the estrone pathway
verfasst von: 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
Publikationsdatum: 20.04.2017
Verlag: Springer US
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 1/2017
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-017-4243-3

Klimawandel und Gesundheit: Was Sie in der Hausarztpraxis wissen müssen und tun können

Springer Medizin

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