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.
Bisphenol A (BPA) is a synthetic compound with structural similarities to the hormone 17β-estradiol. BPA is a major component of polycarbonate plastics and epoxy resins, which are used in the production of plastic containers, metal can linings, dental sealants, thermal receipt paper and household paper products. Incomplete polymerization of BPA as well as exposure to high temperatures and acidic or basic conditions can cause BPA monomers to leach from these products. Therefore, most people are exposed to BPA and levels have been quantified in human urine, blood, saliva, amniotic fluid, placental tissue, colostrum and breast milk. BPA is a weak estrogen and is considered a potential endocrine disrupting compound in humans. Initially it was thought that BPA was rapidly conjugated and excreted from the body. However, free BPA has been detected in human samples indicating that humans are internally exposed to estrogenically active BPA. The length of time that free BPA remains in circulation in the body and the extent to which it accumulates in tissues, such as the breast, is unknown. Given the known sources of BPA exposure, it is likely that lifestyle habits lead to varying levels of BPA exposure. Repeated use of products that contain or are packaged in materials with a high BPA content can lead to higher exposure rates. The same lifestyle choices resulting in high BPA exposure may also lead to high body mass index (BMI); for example, frequent consumption of carbonated soft drinks is associated with a high BMI in women and these beverages are often packaged in plastic bottles or metal cans that may contain BPA. Two recent studies have demonstrated a relationship between BPA levels in urine and obesity in adults and children. Because of the difficulty in measuring BPA in a complex fatty matrix such as milk, few studies have reported on BPA levels in breast milk, and none have examined the relationship between BMI and BPA. In the present study we optimized a sensitive method for assessing free BPA in breast milk and determined whether the levels of BPA were related to characteristics including age, race, BMI, child's age, and number of children nursed. BPA was separated from breast milk samples from 21 nursing women in the U.S. by solid-phase extraction and subsequently analyzed by HPLC-MS/MS. Free BPA was detected in 71% (15/21) of the breast milk samples. The method detection limit in water was determined to be 0.11 ng/mL. Free BPA concentrations were detected ranging from below the method detection limit to 10.81 ng/mL (median 0.49, mean 3.06, SD 3.85 ng/mL). No statistical difference in BPA concentrations was observed between women with a low BMI (< 21.00, n = 10) and a high BMI (> 27.00, n = 11). However, there was a significant association between BPA concentration and race. Caucasian women (n = 14) had significantly higher levels of free BPA in their breast milk than non-Caucasian women (n = 7) (Two-tailed test: t = 2.54, p < 0.05). Citation Format: Stephanie M. Zimmers, Eva P. Browne, Patrick O'Keefe, Douglas L. Anderton, David A. Reckhow, Kathleen F. Arcaro. Determination of free bisphenol A (BPA) concentrations in breast milk of U.S. women using a sensitive LC/MS/MS method. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2520. doi:10.1158/1538-7445.AM2013-2520
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