Circulating estrogens and estrogens within the breast among postmenopausal BRCA1/2 mutation carriers.
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.
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, loudj@mail.nih.gov.
Jennifer T
JT
Loud
Gretchen L
GL
Gierach
Timothy D
TD
Veenstra
Roni T
RT
Falk
Kathryn
K
Nichols
Allison
A
Guttmann
Xia
X
Xu
Mark H
MH
Greene
Mitchell H
MH
Gail
D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000097:blood* / Q000378:metabolism; D004970:Estrone / Q000097:blood* / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D055966:Nipple Aspirate Fluid; D017698:Postmenopause; D017697:Premenopause; D053719:Tandem Mass Spectrometry
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004970:Estrone; D004958:Estradiol