J. Yu

Common genetic variants associated with breast cancer in Korean women and differential susceptibility according to intrinsic subtype.

Background: Recently identified genetic variants from genome-wide association studies (GWAS) on breast cancer have not been validated in Asian populations, except in China. In this study, we sought to confirm the association between known variants and breast cancer in Korean women and further evaluate the associations of individual single nucleotide polymorphisms (SNP) with different intrinsic subtypes of breast cancer. Methods: In total, 3,321 invasive breast cancer patients and 3,500 healthy controls were genotyped for five SNPs by using the TaqMan assay. The SNPs genotyped included rs2046210 (6q25.1), rs2981582 (FGFR2), rs889312 (MAP3K1), rs3803662 (TOX3/TNRC9), and rs4973768 (SLC4A7). Tumors were classified into four intrinsic subtypes based on estrogen receptor (ER), progesterone receptor, HER2, and Ki67 expression. Results: All five SNPs were significantly associated with risk of breast cancer in dominant, recessive, and additive models. ORs per risk allele (95% CI) were 1.29 (1.16–1.43), 1.40 (1.18–1.68), 1.22 (1.06–1.41), 1.52 (1.30–1.77), and 1.20 (1.08–1.33) for rs2046210, rs2981582, rs889312, rs3803662, and rs4973768, respectively. A multigene logistic regression risk model was generated with the SNPs. In subtype analysis, all 5 SNPs were associated with the Luminal A subtype. Two SNPs (rs2046210 and rs3803662) were linked to the ER−HER2+ subtype, and only rs2046210 SNP was associated with the triple-negative subtype. Conclusions: The five SNPs from GWAS were significantly associated with breast cancer risk in Korean women. Associations were heterogeneous according to the intrinsic subtype of breast cancer. Impact: Our result is an important contribution to the literature about genetic susceptibility for breast cancer in nonwhite populations. Cancer Epidemiol Biomarkers Prev; 20(5); 793–8. ©2011 AACR.

Autoantibody to tumor antigen, alpha 2-HS glycoprotein: a novel biomarker of breast cancer screening and diagnosis.

We sought to identify a new serum biomarker for breast cancer screening and diagnosis using stepwise proteomic analysis of sera from breast cancer patients to detect the presence of autoantibodies that react with urinary protein. Two-dimensional immunoblotting was done for screening autoimmunogenic tumor antigens in the urine of breast cancer patients. Reactive spots were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Among urinary proteins separated by two-dimensional electrophoresis, 13 spots showed strong reactivity with pooled sera from breast cancer patients or control sera. By mass spectrometry, we identified α 2-HS glycoprotein (AHSG) as a tumor antigen. Peripheral blood was obtained from 81 women diagnosed with breast cancer before surgery and 73 female donors without evidence of any malignancy for the individual analysis. In one-dimensional Western blot analysis, AHSG autoantibody was detected in 64 of 81 breast cancer patients (79.1%) and in 7 of 73 controls (9.6%). The sensitivity of this test in breast cancer patients was 79.0%. Our results suggest that AHSG and anti-AHSG autoantibody may be useful serum biomarkers for breast cancer screening and diagnosis. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1357–64)

Comparative profiling of plasma proteome from breast cancer patients reveals thrombospondin-1 and BRWD3 as serological biomarkers.

Breast cancer is the most common cancer in women worldwide. It is necessary to identify biomarkers for early detection, to make accurate prognoses, and to monitor for any recurrence of the cancer. In order to identify potential breast cancer biomarkers, we analyzed the plasma samples of women diagnosed with breast cancer and age-matched normal healthy women by mTRAQ-based stable isotope-labeling mass spectrometry. We identified and quantified 204 proteins including thrombospondin-1 (THBS1) and bromodomain and WD repeat-containing protein 3 (BRWD3) which were increased by more than 5-fold in breast cancer plasma. The plasma levels of the two proteins were evaluated by Western blot assay to confirm for their diagnostic value as serum markers. A 1.8-fold increase in BRWD3 was observed while comparing the plasma levels of breast cancer patients (n = 54) with age-matched normal healthy controls (n = 30), and the area under the receiver operating characteristic curve (AUC) was 0.917. THBS1 was detected in pooled breast cancer plasma at the ratio similar to mTRAQ ratio (> 5-fold). The AUC value for THBS1 was 0.875. The increase of THBS1 was more prominent in estrogen receptor negative and progesterone receptor negative patients than receptor-positive patients. Our results are evidence of the diagnostic value of THBS1 in detecting breast cancer. Based on our findings, we suggest a proteomic method for protein identification and quantification lead to effective biomarker discovery.

Extracellular matrix protein 1 regulates cell proliferation and trastuzumab resistance through activation of epidermal growth factor signaling

IntroductionExtracellular matrix protein 1 (ECM1) is a secreted glycoprotein with putative functions in cell proliferation, angiogenesis and differentiation. Expression of ECM1 in several types of carcinoma suggests that it may promote tumor development. In this study, we investigated the role of ECM1 in oncogenic cell signaling in breast cancer, and potential mechanisms for its effects.MethodsIn order to find out the functional role of ECM1, we used the recombinant human ECM1 and viral transduction systems which stably regulated the expression level of ECM1. We examined the effect of ECM1 on cell proliferation and cell signaling in vitro and in vivo. Moreover, tissues and sera of patients with breast cancer were used to confirm the effect of ECM1.ResultsECM1 protein was increased in trastuzumab-resistant (TR) cells, in association with trastuzumab resistance and cell proliferation. Through physical interaction with epidermal growth factor receptor (EGFR), ECM1 potentiated the phosphorylation of EGFR and extracellular signal-regulated kinase upon EGF treatment. Moreover, ECM1-induced galectin-3 cleavage through upregulation of matrix metalloproteinase 9 not only improved mucin 1 expression, but also increased EGFR and human epidermal growth factor receptor 3 protein stability as a secondary signaling.ConclusionsECM1 has important roles in both cancer development and trastuzumab resistance in breast cancer through activation of EGFR signaling.

The electronic structure of epitaxially stabilized 5d perovskite Ca1 − xSrxIrO3 (x = 0, 0.5, and 1) thin films: the role of strong spin–orbit coupling

We have investigated the electronic structure of meta-stable perovskite Ca(1 - x)Sr(x)IrO(3)(x = 0, 0.5, and 1) thin films using transport measurements, optical spectroscopy, and first-principles calculations. We artificially fabricated the perovskite phase of Ca(1 - x)Sr(x)IrO(3), which has a hexagonal or post-perovskite crystal structure in bulk form, by growing epitaxial thin films on perovskite GdScO(3) substrates using an epi-stabilization technique. The transport properties of the perovskite Ca(1 - x)Sr(x)IrO(3) films systematically change from nearly insulating (or semi-metallic) for x = 0 to weakly metallic for x = 1. Due to the extended wavefunctions, 5d electrons are usually delocalized. However, the strong spin-orbit coupling in Ca(1 - x)Sr(x)IrO(3) results in the formation of effective total angular momentum J(eff) = 1/2 and 3/2 states, which puts Ca(1 - x)Sr(x)IrO(3) in the vicinity of a metal-insulator phase boundary. As a result, the electrical properties of the Ca(1 - x)Sr(x)IrO(3) films are found to be sensitive to x and strain.

34.2: PMMA Buffer‐Layer Effects on Electrical Performance of Pentacene OTFTs with a Cross‐linked PVA Gate Insulator on a Flexible Substrate

In this paper we proposed for the first time a technique of poly-methylmethacrylate (PMMA) buffer layer insertion to overcome unsaturated output characteristics of OTFTs with cross-linked poly-vinylalcohol (PVA) gate insulators on a PET substrate. A 3:1 diluted PMMA buffer layer insertion resulted in saturated output characteristics and small shift of a threshold voltage in successive I-V measurements for OTFTs due to the enhancement of surface hydrophobicity on the gate insulator. The electrical performances of a threshold voltage, a subthreshold slope and on-off current ratio have been noticeably improved after PMMA buffer layers insertion. To our best knowledge, the highest mobility of 0.32 cm2/Vsec has been obtained among OTFTs fabricated with polymer gate insulators by spin coating processes on a PET substrate.

Electronic structure of double perovskite A2FeReO6 (A = Ba and Ca): interplay between spin–orbit interaction, electron correlation, and lattice distortion

We have investigated the electronic structure of double perovskites, Ba(2)FeReO(6) (metallic) and Ca(2)FeReO(6) (insulating) using optical and x-ray absorption spectroscopy. By comparing the experimental results with the density functional theory calculations, we found that the electronic structure of Ba(2)FeReO(6) could be determined from the interaction of the electron correlation and spin-orbit coupling. On the other hand, for Ca(2)FeReO(6), the lattice distortion and electron correlation are important in determining the electronic structure. Additionally, the insulating gap in Ca(2)FeReO(6) is realized by the spin-orbit coupling. Our work shows that the subtle interplay of the spin-orbit interaction, electron correlation, and lattice distortion should be taken into account to understand the electronic structure of the 5d transition metal oxides.

A proteomic approach based on multiple parallel separation for the unambiguous identification of an antibody cognate antigen

Autoantibodies obtained from cancer patients have been identified as useful tools for cancer diagnostics, prognostics, and as potential targets for immunotherapy. Serological proteome analysis in combination with 2‐DE is a classic strategy for identification of tumor‐associated antigens in the serum of cancer patients. However, serological proteome analysis cannot always indicate the true antigen out of a complex proteome identified from a single protein spot because the most abundant protein is not always the most antigenic. To address this problem, we utilized multiple parallel separation (MPS) for proteome separation. The common identities present in the fractions obtained using different separation methods were regarded as the true antigens. The merit of our MPS technique was validated using anti‐ARPC2 and anti‐PTEN antibodies. Next, we applied the MPS technique for the identification of glycyl‐tRNA synthetase as the cognate antigen for an autoantibody that was overexpressed in the plasma of breast cancer patients. These results reveal that MPS can unambiguously identify an antibody cognate antigen by reducing false‐positives. Therefore, MPS could be used for the characterization of diagnostic antibodies raised in laboratory animals as well as autoantibodies isolated from diseased patients.

Reproductive factors as risk modifiers of breast cancer in BRCA mutation carriers and high-risk non-carriers

This study was conducted to identify the role of reproductive factors as environmental modifiers for breast cancer (BC) risk in clinic-based, East-Asian BRCA1 and BRCA2 mutation carriers and non-carriers with high-risk criteria of BRCA mutations (family history (FH) of BC, early-onset BC (aged ≤40 years)). A total of 581 women who were BRCA carriers (222 BRCA1 and 359 BRCA2), 1,083 non-carriers with FH, and 886 non-carriers with early-onset BC were enrolled and interviewed to examine the reproductive factors, from 2007 to 2014. The hazard ratio (HR) and its 95% confidence interval (CI) in the weighted Cox regression model were used to calculate the BC risk based on the reproductive factors. Earlier menarche increased BC risk by 3.49-fold in BRCA2 mutation carriers (95%CI=2.03–6.00) and 3.30-fold in non-carriers with FH (95%CI=1.73–6.34), but was insignificantly associated with BRCA1 carriers and non-carriers for early-onset BC (P-heterogeneity=0.047). Higher parity decreased BC risk in BRCA carriers and non-carriers with FH, especially in BRCA1 carriers (HR=0.27, 95% CI=0.09–0.83 for two parity; and HR=0.23, 95%CI=0.05–1.00 for ≥3 parity), but increased the early-onset BC risk (HR=4.63, 95%CI=2.56–8.51 for >3 parity, p-heterogeneity=0.045). Oral contraceptive (OC) use and longer estrogen exposure periods (≥30 years) were associated with an increased risk of early-onset BC (HR=3.99, 95%CI=1.65–9.67; HR=7.69, 95%CI=1.96–25.01), while OC use was not associated with BC risk in other groups and longer estrogen exposure had rather decreased risk for BC risk (both p-heterogeneity<0.001). Several reproductive factors as risk modifiers could heterogeneously be associated with BC among BRCA1/2 mutation carriers, non-carriers with FH, and early-onset BC non-carriers.

Is the high proportion of young age at breast cancer onset a unique feature of Asian breast cancer

PurposeWomen with breast cancer in Asian and Western countries are similar in many respects, but there are also differences, such as in the age at onset and the proportion of breast cancer occurring at younger ages. There is controversy as to whether these differences are due to inter-racial genetic differences or to environmental or other factors.MethodsUsing the Korean Breast Cancer Society’s large breast cancer registry, we investigated the causes of Koreans’ unique breast cancer characteristics by examining the changes in the incidence and proportion of young-onset breast cancer (YBC) in Korea over time. We analyzed data from 108,894 patients to compare characteristics between patients with YBC and non-YBC. For a subtype analysis, we analyzed data from 85,691 patients from 2000.ResultsAmong the 108,894 patients, 17,877 (15.5%) had YBC. The tumors associated with YBC showed aggressive clinicopathologic features. The incidence of breast cancer in Korea has increased over time, and while both YBC and non-YBC increased each year, the increase in non-YBC was more pronounced; thus, the proportion of YBC has decreased over time. By 2020, it appears that the ratio of YBC in Korea will be similar to that in Western countries. The increase in YBC was mainly due to an increase in the luminal A subtype. The incidence of other YBC subtypes did not change over time.ConclusionsOur data suggest that the current high proportion of YBC is probably not a unique feature of breast cancer in Asia but rather a transient phenomenon. Additionally, our results indirectly suggest that there were different causes for breast cancer in different age groups, suggesting the importance of using different approaches for different age groups to establish policies for preventing breast cancer.