Polybrominated diphenyl ethers (PBDEs) are brominated flame retardants that persist in the environment and are present in geographically widespread fish species. PBDE concentrations can be particularly high in resident Chinook salmon (Onchorhynchus tshawytscha) in the Puget Sound, Washington. Although PBDE residues in salmon and other fish are often dominated by lower brominated congeners, these congeners are not produced commercially in the greatest quantity, suggesting bioaccumulation of the lower molecular weight PBDEs or debromination of more fully brominated congeners. We determined the capacity of Chinook liver fractions to debrominate 2,2′, 4,4′,5-pentabromodiphenyl ether (BDE 99), a model PBDE congener readily debrominated by common carp (Cyprinus caprio). Liver subcellular fractions from two strains of Chinook were incubated with BDE 99 prior to liquid/liquid extraction followed by gas chromatography/mass spectrometry analysis (GC/MS analysis) to identify metabolites and debromination products. In contrast to common carp, debromination of BDE 99 to BDE 47 (2,2′,4,4′-tetrabromodiphenyl ether) was not observed in microsomal fractions from either strain of Chinook salmon. However, Chinook salmon liver microsomes from both Chinook strains slowly debrominated BDE 99 to BDE 49 (2,2′, 4,5′-tetrabromodiphenyl ether), a unique debromination product whose formation has not been reported in other fish. Three-year old males belonging to a Rapid River Spring Chinook salmon genetic strain showed a somewhat greater microsomal debromination capacity than older hatchery returning male Chinook, but were still inefficient in the debromination of BDE 99 relative to carp. Microsomal debromination of BDE 99 to BDE 49 was not NADPH-dependent, indicating a lack of cytochrome P450 involvement. By contrast, omission of the reductant dithiothreitol (DTT) from Chinook microsomal preparations resulted in a lack of BDE 99 debromination, suggesting the involvement of a microsomal reductase(s) or deiodinase (DI). Cytosolic fractions from Chinook salmon and Common carp debrominated BDE 99 to BDE 49 in vitro. However, carp cytosolic enzymes preferentially formed BDE 47. In summary, our data indicate significant differences among teleosts with respect to efficiency and metabolite profiles of BDE 99 debromination, and suggest that Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

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This exploratory study demonstrated the feasibility of measuring pro-inflammatory cytokines, adipokines, and angiogenesis factors in human milk, and revealed higher levels of some pro-inflammatory factors, as well as increased leptin levels, among Black as compared with White women.

These proteins may play a role in assessing a woman's risk of pregnancy-associated breast cancer. Because of variable protein concentration among patients and the limited sample size, the results are considered preliminary.

BackgroundFirst full term pregnancy (FFTP) completed at a young age has been linked to low long term breast cancer risk, whereas late FFTP pregnancy age confers high long term risk, compared to nulliparity. Our hypothesis was that proteins linked to breast cancer would be differentially expressed in human milk collected at three time points during lactation based on age at FFTP.MethodsWe analyzed breast milk from 72 lactating women. Samples were collected within 10 days of the onset of lactation (baseline-BL), two months after lactation started and during breast weaning (W). We measured 16 proteins (11 kallikreins (KLKs), basic fibroblast growth factor, YKL-40, neutrophil gelatinase-associated lipocalin and transforming growth factor (TGF) β-1 and -2) associated with breast cancer, most known to be secreted into milk.ResultsDuring lactation there was a significant change in the expression of 14 proteins in women < 26 years old and 9 proteins in women > = 26 at FFTP. The most significant (p < .001) changes from BL to W in women divided by FFTP age (< 26 vs. > = 26) were in KLK3,6, 8, and TGFβ2 in women < 26; and KLK6, 8, and TGFβ2 in women > = 26. There was a significant increase (p = .022) in KLK8 expression from BL to W depending on FFTP age. Examination of DNA methylation in the promoter region of KLK6 revealed high levels of methylation that did not explain the observed changes in protein levels. On the other hand, KLK6 and TGFβ1 expression were significantly associated (r2 = .43, p = .0050).ConclusionsThe expression profile of milk proteins linked to breast cancer is influenced by age at FFTP. These proteins may play a role in future cancer risk.

This review summarizes methods related to the study of human breastmilk in etiologic and biomarkers research. Despite the importance of reproductive factors in breast carcinogenesis, factors that act early in life are difficult to study because young women rarely require breast imaging or biopsy, and analysis of critical circulating factors (e.g. hormones) is often complicated by the requirement to accurately account for menstrual cycle date. Accordingly, novel approaches are needed to understand how events such as pregnancy, breastfeeding, weaning, and post-weaning breast remodeling influence breast cancer risk. Analysis of breastmilk offers opportunities to understand mechanisms related to carcinogenesis in the breast, and to identify risk markers that may inform efforts to identify high-risk women early in the carcinogenic process. In addition, analysis of breastmilk could have value in early detection or diagnosis of breast cancer. In this article we describe the potential for using breastmilk to characterize the microenvironment of the lactating breast with the goal of advancing research on risk assessment, prevention, and detection of breast cancer.

BackgroundThe DNA methyltransferase 1 inhibitor, 5-Aza-2′-deoxycytidine (5-Aza-dC) is a potential treatment for breast cancer. However, not all breast tumors will respond similarly to treatment with 5-Aza-dC, and little is known regarding the response of hormone-resistant breast cancers to 5-Aza-dC.MethodsWe demonstrate that 5-Aza-dC-treatment has a stronger effect on an estrogen receptor-negative, Tamoxifen-selected cell line, TMX2-28, than on the estrogen receptor-positive, MCF7, parental cell line. Using data obtained from the HM450 Methylation Bead Chip, pyrosequencing, and RT-qPCR, we identified a panel of genes that are silenced by promoter methylation in TMX2-28 and re-expressed after treatment with 5-Aza-dC.ResultsOne of the genes identified, tumor associated calcium signal transducer 2 (TACSTD2), is altered by DNA methylation, and there is evidence that in some cancers decreased expression may result in greater proliferation. Analysis of DNA methylation of TACSTD2 and protein expression of its product, trophoblast antigen protein 2 (TROP2), was extended to a panel of primary (n = 34) and recurrent (n = 34) breast tumors. Stratifying tumors by both recurrence and ER status showed no significant relationship between TROP2 levels and TACSTD2 methylation. Knocking down TACSTD2 expression in MCF7 increased proliferation however; re-expressing TACSTD2 in TMX2-28 did not inhibit proliferation, indicating that TACSTD2 re-expression alone was insufficient to explain the decreased proliferation observed after treatment with 5-Aza-dC.ConclusionsThese results illustrate the complexity of the TROP2 signaling network. However, TROP2 may be a valid therapeutic target for some cancers. Further studies are needed to identify biomarkers that indicate how TROP2 signaling affects tumor growth and whether targeting TROP2 would be beneficial to the patient.Electronic supplementary materialThe online version of this article (10.1186/s12935-018-0589-9) contains supplementary material, which is available to authorized users.