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Circulating estrogens and estrogens within the breast among postmenopausal BRCA1/2 mutation carriers

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Abstract

Accurately quantifying parent estrogens (PE) estrone (E1) and estradiol (E2) and their metabolites (EM) within breast tissue and serum may permit detailed investigations of their contributions to breast carcinogenesis among BRCA1/2 mutation carriers. We conducted a study of PE/EM in serum, nipple aspirate fluid (NAF), and ductal lavage supernatant (DLS) among postmenopausal BRCA1/2 mutation carriers. PE/EM (conjugated and unconjugated) were measured in paired serum/NAF (n = 22 women) and paired serum/DLS samples (n = 24 women) using quantitative liquid chromatography–tandem mass spectrometry (LC/MS/MS). The relationships between serum and tissue-specific PE/EM were measured using Pearson’s correlation coefficients. Conjugated forms of PE/EM constituted the majority of estrogen in serum (88 %), NAF (59 %) and DLS (69 %). PE/EM in NAF and serum were highly correlated [E1 (r = 0.97, p < 0.0001), E2 (r = 0.90, p < 0.0001) and estriol (E3) (r = 0.74, p < 0.0001)] as they were in DLS and serum [E1 (r = 0.92, p < 0.0001; E2 (r = 0.70, p = 0.0001; E3 (r = 0.67, p = 0.0004)]. Analyses of paired total estrogen values for NAF and serum, and DLS and serum yielded ratios of 0.22 (95 % CI 0.19–0.25) and 0.28 (95 % CI 0.24–0.32), respectively. This report is the first to employ LC/MS/MS to quantify PE/EM in novel breast tissue-derived biospecimens (i.e., NAF and DLS). We demonstrate that circulating PE and EM are strongly and positively correlated with tissue-specific PE and EM measured in NAF and DLS among postmenopausal BRCA1/2 mutation carriers. If confirmed, future etiologic studies could utilize the more readily obtainable serum hormone levels as a reliable surrogate measure of exposure at the tissue level.

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Abbreviations

BRCA1/2:

Breast Cancer genes 1 and 2

PE:

Parent estrogen

E1:

Estrone

E2:

Estradiol

E3:

Estriol

EM:

Estrogen metabolites

TE:

Total estrogens, conjugated + unconjugated

NAF:

Nipple aspirate fluid

DLS:

Ductal lavage supernatant

LC/MS/MS:

Liquid chromatography–tandem mass spectrometry

DNA:

Deoxyribonucleic acid

ER:

Estrogen receptor

NCI:

National Cancer Institute

BIS:

Breast Imaging Study

MRI:

Magnetic resonance imaging

IRB:

Institutional Review Board

2-OHE1:

2-Hydroxyestrone

2-MeOE1:

2-Methoxyestrone

2-OHE2:

2-Hydroxyestradiol

2-MeOE2:

2-Methoxyestradiol

3-MeOE1:

2-Hydroxyestrone-3-methyl ether

4-OHE1:

4-Hydroxyestrone

4-MeOE1:

4-Methoxyestrone

4-MeOE2:

4-Methoxyestradiol

16α-OHE1:

16α-Hydroxyestrone

17-epiE3:

17-Epiestriol

16-ketoE2:

16-Ketoestradiol

16-epiE3:

16-Epiestriol

SI-EM:

Stable isotope-labeled estrogens

Estrone-13C6:

Estrone-13,14,15,16,17,18-13C6

17β-estradiol-13C6:

17β-Estradiol-13,14,15,16,17,18-13C6

d3-E3:

Estriol-2,4,17-d3

d5-2-OHE2:

2-Hydroxyestradiol-1,4,16,16,17-d5

d5-2-MeOE2:

2-Methoxyestradiol-1,4,16,16,17-d5

d3-16-epiE3:

16-Epiestriol-2,4,16-d3

ICC:

Intra-class correlation coefficients

BMI:

Body mass index

RRSO:

Risk reducing salpingo-oophorectomy

SD:

Standard deviation

RIA:

Radioimmunoassy

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Acknowledgments

The Breast Imaging Study (NCI Protocol #01-C-0009). We wish to thank Ruthann Giusti, Christine Mueller and Phuong L. Mai for clinical support; Phuong L. Mai for reviewing the manuscript; Nicole Dupree, Jason Hu, Beth Mittl, and Usha Singh for their help in data preparation. Special thanks to all our study participants; without whose cooperation this study could not have been done. This project was supported by the Intramural Research Program of the National Cancer Institute, by contracts NO2-CP-11019-50 and NO2-CP-65504-50 with Westat, Inc. and by a Molecular Epidemiology Award from the Division of Cancer Epidemiology and Genetics, National Cancer Institute. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN261200800001E. By acceptance of this article, the publisher or recipient acknowledges the right of the United States Government to retain a nonexclusive, royalty-free license and to any copyright covering the article. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the United States Government.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Clinical Genetics Branch (CGB), Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, 9609 Medical Center Drive, Room 6E536, Bethesda, MD, 20850-9772, USA

    Jennifer T. Loud, Allison Guttmann & Mark H. Greene

  2. Hormonal and Reproductive Epidemiology Branch (HREB), Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, 9609 Medical Center Drive, Room 7E108, Bethesda, MD, 20850-9774, USA

    Gretchen L. Gierach & Roni T. Falk

  3. Biostatistics Branch (BB), Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, 9609 Medical Center Drive, 7E138, Bethesda, MD, 20850-9780, USA

    Mitchell H. Gail

  4. Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC Frederick, Inc., 1050 Boyles St., Bldg. 469/163, Frederick, MD, 21702, USA

    Timothy D. Veenstra & Xia Xu

  5. Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, 21702, USA

    Timothy D. Veenstra & Xia Xu

  6. WESTAT Corporation, 1450 Research Blvd., Rockville, MD, 20850, USA

    Kathryn Nichols

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  1. Jennifer T. Loud
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  2. Gretchen L. Gierach
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  3. Timothy D. Veenstra
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  7. Xia Xu
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  9. Mitchell H. Gail
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Correspondence to Jennifer T. Loud or Mark H. Greene.

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Loud, J.T., Gierach, G.L., Veenstra, T.D. et al. Circulating estrogens and estrogens within the breast among postmenopausal BRCA1/2 mutation carriers. Breast Cancer Res Treat 143, 517–529 (2014). https://doi.org/10.1007/s10549-013-2821-6

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  • DOI: https://doi.org/10.1007/s10549-013-2821-6

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