Biomarker Commons

Identifying cancer biomarkers by network-constrained support vector machines.

BMC Syst Biol. 2011;5:161

Authors: Chen L, Xuan J, Riggins RB, Clarke R, Wang Y

Abstract
BACKGROUND: One of the major goals in gene and protein expression profiling of cancer is to identify biomarkers and build classification models for prediction of disease prognosis or treatment response. Many traditional statistical methods, based on microarray gene expression data alone and individual genes' discriminatory power, often fail to identify biologically meaningful biomarkers thus resulting in poor prediction performance across data sets. Nonetheless, the variables in multivariable classifiers should synergistically interact to produce more effective classifiers than individual biomarkers.
RESULTS: We developed an integrated approach, namely network-constrained support vector machine (netSVM), for cancer biomarker identification with an improved prediction performance. The netSVM approach is specifically designed for network biomarker identification by integrating gene expression data and protein-protein interaction data. We first evaluated the effectiveness of netSVM using simulation studies, demonstrating its improved performance over state-of-the-art network-based methods and gene-based methods for network biomarker identification. We then applied the netSVM approach to two breast cancer data sets to identify prognostic signatures for prediction of breast cancer metastasis. The experimental results show that: (1) network biomarkers identified by netSVM are highly enriched in biological pathways associated with cancer progression; (2) prediction performance is much improved when tested across different data sets. Specifically, many genes related to apoptosis, cell cycle, and cell proliferation, which are hallmark signatures of breast cancer metastasis, were identified by the netSVM approach. More importantly, several novel hub genes, biologically important with many interactions in PPI network but often showing little change in expression as compared with their downstream genes, were also identified as network biomarkers; the genes were enriched in signaling pathways such as TGF-beta signaling pathway, MAPK signaling pathway, and JAK-STAT signaling pathway. These signaling pathways may provide new insight to the underlying mechanism of breast cancer metastasis.
CONCLUSIONS: We have developed a network-based approach for cancer biomarker identification, netSVM, resulting in an improved prediction performance with network biomarkers. We have applied the netSVM approach to breast cancer gene expression data to predict metastasis in patients. Network biomarkers identified by netSVM reveal potential signaling pathways associated with breast cancer metastasis, and help improve the prediction performance across independent data sets.

PMID: 21992556 [PubMed - indexed for MEDLINE]

Gradually implemented new biomarkers for prognostication of breast cancer: complete case analysis may introduce bias.

J Clin Epidemiol. 2012 May;65(5):568-71

Authors: Bhoo Pathy N, Uiterwaal CS, Taib NA, Verkooijen HM, Yip CH

Abstract
OBJECTIVE: Many recent studies investigated the prognostic value of new biomarkers in breast cancer using data from cancer registries. Some of these studies were conducted using only patients for whom biomarker status was available (or tested). Using human epidermal growth factor receptor 2 (HER2) as an example, we determined whether testing for a recently introduced biomarker was associated with the outcome of women with breast cancer.
STUDY DESIGN AND SETTING: We included 910 women with newly diagnosed breast cancer in a tertiary academic hospital in Kuala Lumpur, Malaysia, between 2005 and 2007. Individual 2-year absolute mortality risk was estimated using Cox regression analysis. Logistic regression was used to assess the association between the absolute mortality risk and assessment of HER2 status.
RESULTS: There was a significant inverted U-shaped association between predicted mortality risk and HER2 status determination. Compared with patients with the lowest predicted mortality risk (quintile 1), patients with highest predicted mortality risk (last quintile) were significantly less likely to be tested for HER2 status, whereas those with intermediate predicted mortality risk (quintile 3) were more likely to be tested.
CONCLUSION: Breast cancer prognostication using only patients with available biomarker status may lead to invalid results.

PMID: 22269329 [PubMed - indexed for MEDLINE]

Pathologic features and molecular phenotype by patient age in a large cohort of young women with breast cancer.

Breast Cancer Res Treat. 2012 Feb;131(3):1061-6

Authors: Collins LC, Marotti JD, Gelber S, Cole K, Ruddy K, Kereakoglow S, Brachtel EF, Schapira L, Come SE, Winer EP, Partridge AH

Abstract
Prior studies have suggested a higher prevalence of high grade, ER-negative, HER2-positive, and basal-like carcinomas in young women with breast cancer. However, the precise distribution of poor prognostic features in this population remains unclear. We examined the pathologic features and distribution of molecular phenotype in relation to patient age in a large group of young women (≤40 years) with invasive breast cancer. Medical records were reviewed for clinical characteristics, tumor stage, and receptor status. Pathologic features, including those features associated with basal-like carcinomas, were examined by central review. Using tumor grade and biomarker expression, cancers were categorized as luminal A (ER+ and/or PR+ and HER2-, histologic grade 1 or 2); luminal B (ER+ and/or PR+ and HER2+, or ER and/or PR+, HER2- and grade 3); HER2 (ER and PR- and HER2+); and triple negative (ER-, PR-, and HER2-). Among 399 women of ≤40 years, 33% had luminal A tumors, 35% luminal B, 11% HER2 (ER-negative), and 21% triple negative. Compared to published results for all breast cancers, a greater proportion of young women had luminal B tumors, and a lesser proportion had luminal A. There were no significant differences in molecular phenotype, tumor stage or grade among the different age groups of young women. However, this population of young women presented with a different distribution of molecular phenotypes compared to the general population of women with breast cancer. These findings may have implications with regard to the etiology and prognosis of breast cancer in young women.

PMID: 22080245 [PubMed - indexed for MEDLINE]

A short-term biomarker modulation study of simvastatin in women at increased risk of a new breast cancer.

Breast Cancer Res Treat. 2012 Feb;131(3):915-24

Authors: Higgins MJ, Prowell TM, Blackford AL, Byrne C, Khouri NF, Slater SA, Jeter SC, Armstrong DK, Davidson NE, Emens LA, Fetting JH, Powers PP, Wolff AC, Green H, Thibert JN, Rae JM, Folkerd E, Dowsett M, Blumenthal RS, Garber JE, Stearns V

Abstract
Observational studies have demonstrated a decreased incidence of cancers among users of HMG CoA reductase inhibitors (statins) and a reduced risk of recurrence among statin users diagnosed with early stage breast cancer. We initiated a prospective study to identify potential biomarkers of simvastatin chemopreventive activity that can be validated in future trials. The contralateral breast of women with a previous history of breast cancer was used as a high-risk model. Eligible women who had completed all planned treatment of a prior stage 0-III breast cancer received simvastatin 40 mg orally daily for 24-28 weeks. At baseline and end-of-study, we measured circulating concentrations of high-sensitivity C-reactive protein (hsCRP), estrogens, and fasting lipids; breast density on contralateral breast mammogram; and quality of life by Rand Short Form 36-Item health survey. Fifty women were enrolled with a median age of 53 years. Total cholesterol, LDL cholesterol, triglyceride, and hsCRP fell significantly during the study (P values < 0.001, <0.001, 0.003, and 0.05, respectively). Estrone sulfate concentrations decreased with simvastatin treatment (P = 0.01 overall), particularly among post-menopausal participants (P = 0.006). We did not observe a significant change in circulating estradiol or estrone concentrations, contralateral mammographic breast density, or reported physical functioning or pain scores. This study demonstrates the feasibility of short-term biomarker modulation studies using the contralateral breast of high-risk women. Simvastatin appears to modulate estrone sulfate concentrations and its potential chemopreventive activity in breast cancer warrants further investigation.

PMID: 22076478 [PubMed - indexed for MEDLINE]

A phase I/II prospective, single arm trial of gefitinib, trastuzumab, and docetaxel in patients with stage IV HER-2 positive metastatic breast cancer.

Breast Cancer Res Treat. 2012 Feb;131(3):899-906

Authors: Somlo G, Martel CL, Lau SK, Frankel P, Ruel C, Gu L, Hurria A, Chung C, Luu T, Morgan R, Leong L, Koczywas M, McNamara M, Russell CA, Kane SE

Abstract
Inhibition of the HER-2 pathway via the monoclonal antibody trastuzumab has had a major impact in treatment of HER-2 positive breast cancer, but de novo or acquired resistance may reduce its effectiveness. The known interplay between the epidermal growth factor receptor (EGFR) and HER-2 receptors and pathways creates a rationale for combined anti-EGFR and anti-HER-2 therapy in HER-2 positive metastatic breast cancer (MBC), and toxicities associated with the use of multiple chemotherapeutic agents together with biological therapies may also be reduced. We conducted a prospective, single arm, phase I/II trial to determine the efficacy and toxicity of the combination of trastuzumab with the EGFR inhibitor gefitinib and docetaxel, in patients with HER-2 positive MBC. The maximum tolerated dose (MTD) was determined in the phase I portion. The primary end point of the phase II portion was progression-free survival (PFS). Immunohistochemical analysis of biomarker expression of the PKA-related proteins cAMP response element-binding protein (CREB), phospho-CREB and DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32 kDa) plus t-DARPP (the truncated isoform of DARPP-32); PTEN; p-p70 S6K; and EGFR was conducted on tissue from metastatic sites. Nine patients were treated in the phase I portion of the study and 22 in the phase II portion. The MTD was gefitinib 250 mg on days 2-14, trastuzumab 6 mg/kg, and docetaxel 60 mg/m(2) every 21 days. For the 29 patients treated at the MTD, median PFS was 12.7 months, with complete and partial response rates of 18 and 46%, and a stable disease rate of 29%. No statistically significant correlation was found between response and expression of any biomarkers. We conclude that the combination of gefitinib, trastuzumab, and docetaxel is feasible and effective. Expression of the biomarkers examined did not predict outcome in this sample of HER-2 overexpressing metastatic breast cancer.

PMID: 22042372 [PubMed - indexed for MEDLINE]

Serum human telomerase reverse transcriptase: a novel biomarker for breast cancer diagnosis.

Int J Clin Oncol. 2011 Dec;16(6):617-22

Authors: Porika M, Tippani R, Bollam SR, Panuganti SD, Thamidala C, Abbagani S

Abstract
BACKGROUND: Telomerase is a ribonucleoprotein complex composed mainly of a reverse transcriptase catalytic subunit, telomerase reverse transcriptase (hTERT). Expression of hTERT confers telomerase activity, indicating that hTERT is the rate-limiting component of human telomerase. The aim of the present study was to investigate the diagnostic implications of hTERT in the serum of breast cancer patients.
METHODS: The study was conducted on 159 breast cancer patients and 41 healthy volunteers as controls. The evaluation of hTERT, cancer antigen 15.3 and carcinoembryonic antigen were performed by enzyme-linked immunosorbent assay, and analysed for their correlation with the patient's clinicopathological features.
RESULTS: 27 of 52 (51.9%) patients with stage I breast cancer, 31 of 40 (77.5%) with stage II and 30 of 34 (88.2%) patients with stage III exhibited elevated hTERT levels. Serum hTERT levels showed significantly higher mean values in patients with breast cancer than healthy individuals. The sensitivity and specificity of hTERT in cancer diagnosis was 68.9 and 83.3%, respectively, which is significantly higher than conventional markers. The expression of serum hTERT was significantly correlated with telomerase activity in breast cancer tissues. Pretreatment serum hTERT levels showed a significant correlation with clinical stage, while correlation with nodal status and tumor size were marginal and no correlation was found with family history and age.
CONCLUSION: Serum hTERT is useful for diagnosing and assessing the clinical stage of breast cancer and is superior to conventional markers. Therefore, serum hTERT could have a potential application as a novel biomarker for breast cancer diagnosis.

PMID: 21526393 [PubMed - indexed for MEDLINE]

Primary tumor classification according to methylation pattern is prognostic in patients with early stage ER-negative breast cancer.

Breast Cancer Res Treat. 2012 Feb;131(3):859-69

Authors: van Hoesel AQ, van de Velde CJ, Kuppen PJ, Putter H, de Kruijf EM, van Nes JG, Giuliano AE, Hoon DS

Abstract
Breast cancer patients with similar clinical stage may experience different disease outcomes. Aberrant DNA methylation of primary breast tumors can have impact on the clinical outcome. This study aimed to assess clinical utility of tumor-specific methylated sequences (MINT17, 31) and tumor-related gene (RARβ2) methylation classification in primary breast tumors. Absolute quantitative assessment of methylated alleles (AQAMA) was used to determine the methylation index (MI) of MINT17, MINT31, and RARß2 in 242 primary tumors of early stage breast cancer patients. Patients were classified into three methylation groups: meth-N, with normal methylation levels of all biomarkers; meth-L, with one biomarker hypermethylation; and meth-H, with hypermethylation of >1 biomarker. Disease outcome of methylation groups was compared during follow-up. MI of all biomarkers was successfully obtained in 237 tumors of which 79 (33%) were classified as meth-N, 86 (36%) as meth-L, and 72 (30%) as meth-H. Meth-H status was a risk factor for distant recurrence (DR) (log-rank P = 0.007) and shorter disease-free survival (DFS) (log-rank P = 0.039). Methylation classification had strongest prognostic value for patients with ER-negative tumors. In multivariate analysis (n = 222), ER-negative meth-H patients had a 4.1-fold increased risk of DR (95% CI 1.80-9.59; meth-N HR 1.0, P = 0.001), a 4.2-fold increased risk of overall recurrence (OR) (95% CI 1.88-9.47; meth-N HR 1.0, P = 0.001), and a 3.1-fold shorter DFS (95% CI 1.57-5.98; meth-N HR 1.0, P = 0.003). Methylation classification of primary breast cancer is an independent prognostic factor for disease outcome in patients with ER-negative tumors. The study's findings will have to be confirmed in an independent dataset.

PMID: 21479925 [PubMed - indexed for MEDLINE]

Dietary supplements and natural products in breast cancer trials.

Front Biosci (Elite Ed). 2012;4:546-67

Authors: Kado K, Forsyth A, Patel PR, Schwartz JA

Abstract
The association between breast cancer and modifiable health behaviors is well supported. At least one-half of all cancers are suggested to have a dietary component. It is not surprising therefore that many of the dietary agents and natural health products that have attracted the attentions of scientists and practitioners are now moving into clinical trials. In this report, we review 65 clinical intervention trials evaluating over 30 dietary supplements and natural health products for use in breast cancer. The products being tested in these trials fall broadly into the following categories: (i) vitamins, minerals, cofactors; (ii) herbal extracts; (iii) amino acids; (iv) fatty acids; (v) animal products; (vi) probiotics; (vii) phytochemicals; and (viii) combination formulations. Trial outcome measures include risk modification, efficacy testing (with dietary supplements alone or dietary supplement-anticancer drug combinations), toxicity reduction, biomarker identification, symptom management, and quality of life parameters. The wide range of interests in natural product testing at the clinical trial level supports the potential utility of these agents in the breast cancer prevention, treatment, and management regimens of the future.

PMID: 22201894 [PubMed - indexed for MEDLINE]

Soluble human leukocyte antigen-G expression in patients with ductal and lobular breast malignancy.

Anticancer Res. 2012 Mar;32(3):1021-6

Authors: Provatopoulou X, Kalogera E, Sagkriotis A, Zagouri F, Nonni A, Zografos GC, Gounaris A

Abstract
BACKGROUND: Human leukocyte antigen-G (HLA-G) has been closely associated with diagnosis and prognosis in many types of human cancer. The current study aims to investigate soluble (s) HLA-G expression in patients with breast malignancy.
PATIENTS AND METHODS: sHLA-G plasma expression was determined in 120 patients with breast cancer and 40 healthy controls using enzyme-linked immunosorbent assay.
RESULTS: Plasma sHLA-G levels were significantly higher in breast cancer patients compared to healthy controls (p<0.001), with an area under the receiver operating characteristic (ROC) curve of 0.735 (95% Confidence interval=0.630-0.841, p<0.001). Significantly increased sHLA-G expression was detected in patients with mixed type of coexisting ductal and lobular breast lesions, compared to patients with pure ductal carcinoma or pure lobular neoplasia (p<0.05).
CONCLUSION: sHLA-G expression is closely associated with the histological type of breast cancer. Our findings support the application of sHLA-G as a potential biomarker in body fluids for preoperative breast cancer detection and diagnosis.

PMID: 22399626 [PubMed - indexed for MEDLINE]

Proteomic analysis of exosome-like vesicles derived from breast cancer cells.

Anticancer Res. 2012 Mar;32(3):847-60

Authors: Palazzolo G, Albanese NN, DI Cara G, Gygax D, Vittorelli ML, Pucci-Minafra I

Abstract
BACKGROUND/AIM: The phenomenon of membrane vesicle-release by neoplastic cells is a growing field of interest in cancer research, due to their potential role in carrying a large array of tumor antigens when secreted into the extracellular medium. In particular, experimental evidence show that at least some of the tumor markers detected in the blood circulation of mammary carcinoma patients are carried by membrane-bound vesicles. Thus, biomarker research in breast cancer can gain great benefits from vesicle characterization.
MATERIALS AND METHODS: Conditioned medium was collected from serum starved MDA-MB-231 sub-confluent cell cultures and exosome-like vesicles (ELVs) were isolated by ultracentrifugation. Ultrastructural analysis of ELVs was performed by transmission electron microscopy (TEM) and the purity of fraction was confirmed by western blotting assays. Proteomic profile of ELVs was carried out by 2 D-PAGE and protein identification performed by MALDI-ToF Mass Spectrometry.
RESULTS: On the basis of ultrastructural and immunological characterization, the isolated vesicles have been classified as exosome-like vesicles (ELVs). The proteomic investigation showed a distinctive protein profile of the ELVs, in comparison to the whole cell lisates (WCL) proteome, which could be instrumental for cancer progression. The proteins were clustered into functional categories, according to the current bioinformatics resources and a Venn diagram was constructed based on these clusters.
CONCLUSION: It is reasonable to assume that vesicle production allows neoplastic cells to exert different effects, according to the possible acceptor targets. For instance, vesicles could potentiate the malignant properties of adjacent neoplastic cells or activate non-tumoral cells. Moreover, vesicles could convey signals to immune cells and surrounding stroma cells. The present study may significantly contribute to the knowledge of the vesiculation phenomenon, which is a critical device for trans cellular communication in cancer.

PMID: 22399603 [PubMed - indexed for MEDLINE]

The role of microRNA-binding site polymorphisms in DNA repair genes as risk factors for bladder cancer and breast cancer and their impact on radiotherapy outcomes.

Carcinogenesis. 2012 Mar;33(3):581-6

Authors: Teo MT, Landi D, Taylor CF, Elliott F, Vaslin L, Cox DG, Hall J, Landi S, Bishop DT, Kiltie AE

Abstract
MicroRNAs (miRNAs) are involved in post-transcriptional regulation of gene expression through binding to messenger RNAs (mRNA) thereby promoting mRNA degradation or altered translation. A single-nucleotide polymorphism (SNP) located within a miRNA-binding site could thus alter mRNA translation and influence cancer risk and treatment response. The common SNPs located within the 3'-untranslated regions of 20 DNA repair genes were analysed for putative miRNA-binding sites using bioinformatics algorithms, calculating the difference in Gibbs free binding energy (ΔΔG) for each wild-type versus variant allele. Seven SNPs were selected to be genotyped in germ line DNAs both from a bladder cancer case-control series (752 cases and 704 controls) and 202 muscle-invasive bladder cancer radiotherapy cases. The PARP-1 SNP rs8679 was also genotyped in a breast cancer case-control series (257 cases and 512 controls). Without adjustment for multiple testing, multivariate analysis demonstrated an association with increased bladder cancer risk with PARP1 rs8679 (P(trend) = 0.05) while variant homozygotes of PARP1 rs8679 were also noted to have an increased breast cancer risk (P = 0.03). In the radiotherapy cases, carriers of the RAD51 rs7180135 minor allele had improved cancer-specific survival (hazard ratio 0.52, 95% confidence interval 0.31-0.87, P = 0.01). This is the first report of associations between DNA repair gene miRNA-binding site SNPs with bladder and breast cancer risk and radiotherapy outcomes. If validated, these findings may give further insight into the biology of bladder carcinogenesis, allow testing of the RAD51 SNP as a potential predictive biomarker and also reveal potential targets for new cancer treatments.

PMID: 22166496 [PubMed - indexed for MEDLINE]

Why the term 'low-grade ductal carcinoma in situ' should be changed to 'borderline breast disease': diagnostic and clinical implications.

Womens Health (Lond Engl). 2012 Jan;8(1):57-62

Authors: Masood S

Abstract
During the last several years, increased public awareness, advances in breast imaging and enhanced screening programs have led to early breast cancer detection and attention to cancer prevention. The number of image-detected biopsies has increased, and pathologists are expected to provide more information with smaller tissue samples. These biopsies have resulted in detection of increasing numbers of high-risk proliferative breast disease and in situ cancers. The general hypothesis is that some forms of breast cancers may arise from established forms of ductal carcinoma in situ and atypical ductal hyperplasia, and possibly from more common forms of ductal hyperplasia. However, this is an oversimplification of a very complex process given the fact that the majority of breast cancers appear to arise de novo or from a yet unknown precursor lesion. Currently, atypical ductal hyperplasia and ductal carcinoma in situ are considered as morphologic risk factors and precursor lesions for breast cancer. However, morphologic distinction between these two entities has remained a real issue that continues to lead to overdiagnosis and overtreatment. Aside from morphologic similarities between atypical ductal hyperplasia and low-grade ductal carcinoma in situ, biomarker studies and molecular genetic testing have shown that morphologic overlaps are reflected at the molecular level and raise questions about the validity of separating these two entities. It is hoped that as we better understand the genetic basis of these entities in relation to ultimate patient outcome, the suggested use of the term 'borderline breast disease' can minimize the number of patients who are subject to overtreatment.

PMID: 22171775 [PubMed - indexed for MEDLINE]

Clinicopathologic and prognostic implications of progranulin in breast carcinoma.

Chin Med J (Engl). 2011 Jul 5;124(13):2045-50

Authors: Li LQ, Huang HL, Ping JL, Wang XH, Zhong J, Dai LC

Abstract
BACKGROUND: Progranulin is a newly discovered 88-kDa glycoprotein originally purified from the highly tumorigenic mouse teratoma-derived cell line PC. Its expression is closely correlated with the development and metastasis of several cancers. However, no immunohistochemical evidence currently exists to correlate progranulin expression with clinicopathologic features in breast carcinoma biopsies, and the role of progranulin as a new marker of metastatic risk and prognosis in breast cancer has not yet been studied. The aim of this study was to investigate the clinicopathologic and prognostic implications of progranulin expression in breast carcinoma and its correlation with tumor angiogenesis.
METHODS: Progranulin expression was determined immunohistochemically in 183 surgical specimens from patients with breast cancer and 20 tissue samples from breast fibroadenomas. The tumor angiogenesis-related biomarker, vascular endothelial growth factor was assayed and microvessel density was assessed by counting vascular endothelial cells in tumor tissues labeled with endoglin antibody. The relationship between progranulin expression and the clinicopathologic data were analyzed.
RESULTS: Progranulin proteins were overexpressed in breast cancer. The level of progranulin expression was significantly correlated with tumor size (P = 0.004), lymph node metastasis (P < 0.001) and TNM staging (P < 0.001). High progranulin expression was associated with higher tumor angiogenesis, reflected by increased vascular endothelial growth factor expression (P < 0.001) and higher microvessel density (P = 0.002).
CONCLUSION: Progranulin may be a valuable marker for assessing the metastasis and prognosis of breast cancer, and could provide the basis for new combination regimens with antiangiogenic activity.

PMID: 22088468 [PubMed - indexed for MEDLINE]

Expression level of novel tumor suppressor gene FATS is associated with the outcome of node positive breast cancer.

Chin Med J (Engl). 2011 Sep;124(18):2894-8

Authors: Zhang J, Gu L, Zhao LJ, Zhang XF, Qiu L, Li Z

Abstract
BACKGROUND: Recently, we reported the identification of a previously uncharacterized and evolutionarily conserved gene, fragile-site associated tumor suppressor (FATS), at a frequently deleted region in irradiation (IR)-induced tumors. However, the role of FATS in breast cancer development and its clinical significance has not been defined. The aim of this study was to determine the role of FATS in breast cancer development and to evaluate its clinical significance in breast cancer.
METHODS: The expression level of FATS mRNA was determined in 106 breast carcinomas and 23 paired normal breast tissues using quantitative real time reverse transcription-polymerase chain reaction (RT-PCR). The relationship between FATS expression and clinicopathological parameters were also analyzed.
RESULTS: The mRNA level of FATS was down-regulated in breast cancer compared with paired normal tissues. Low expression of FATS was correlated with high nuclear grade. There was a tendency to a favorable outcome for patients with high expression of FATS (P = 0.346). However, low expression of FATS was associated with poor outcome of breast cancer patients with node positive (P = 0.011). Furthermore, the mRNA level of FATS showed an independent value in predicting the outcome of breast cancer patients with positive lymph nodes.
CONCLUSION: FATS is involved in the carcinogenesis and development of breast cancer and could be a potential biomarker and prognostic factor for breast cancer therapy.

PMID: 22040499 [PubMed - indexed for MEDLINE]

MUC16 induced rapid G2/M transition via interactions with JAK2 for increased proliferation and anti-apoptosis in breast cancer cells.

Oncogene. 2012 Feb 16;31(7):805-17

Authors: Lakshmanan I, Ponnusamy MP, Das S, Chakraborty S, Haridas D, Mukhopadhyay P, Lele SM, Batra SK

Abstract
MUC16/CA125 is a tumor marker currently used in clinics for the follow-up of patients with ovarian cancer. However, MUC16 expression is not entirely restricted to ovarian malignancies and has been reported in other cancers including breast cancer. Although it is well established as a biomarker, function of MUC16 in cancer remains to be elucidated. In the present study, we investigated the role of MUC16 in breast cancer and its underlying mechanisms. Interestingly, our results showed that MUC16 is overexpressed in breast cancer tissues whereas not expressed in non-neoplastic ducts. Further, stable knockdown of MUC16 in breast cancer cells (MDA MB 231 and HBL100) resulted in significant decrease in the rate of cell growth, tumorigenicity and increased apoptosis. In search of a mechanism for breast cancer cell proliferation we found that MUC16 interacts with the ezrin/radixin/moesin domain-containing protein of Janus kinase (JAK2) as demonstrated by the reciprocal immunoprecipitation method. These interactions mediate phosphorylation of STAT3 (Tyr705), which might be a potential mechanism for MUC16-induced proliferation of breast cancer cells by a subsequent co-transactivation of transcription factor c-Jun. Furthermore, silencing of MUC16 induced G2/M arrest in breast cancer cells through downregulation of Cyclin B1 and decreased phosphorylation of Aurora kinase A. This in turn led to enhanced apoptosis in the MUC16-knockdown breast cancer cells through Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated extrinsic apoptotic pathway with the help of c-Jun N-terminal kinase signaling. Collectively, our results suggest that MUC16 has a dual role in breast cancer cell proliferation by interacting with JAK2 and by inhibiting the apoptotic process through downregulation of TRAIL.

PMID: 21785467 [PubMed - indexed for MEDLINE]

Advancements in the use of blood tests for cancer screening in women at high risk for endometrial and breast cancer.

Future Oncol. 2011 Dec;7(12):1399-414

Authors: Ambeba E, Linkov F

Abstract
Several years ago, it was argued that the identification of serum biomarkers is one of the most promising approaches for the detection of early-stage malignant or even premalignant lesions. In this review, the need to establish better monitoring protocols is described for obese women who are at higher risk for the development of malignancies commonly associated with excess weight; specifically endometrial and postmenopausal breast cancer. These cancers have been chosen for this review article as our aim was to focus on female cancers that have been linked with obesity. Cancer screening is essential in detecting disease in its earliest stage in order to reduce morbidity and mortality; however, effective screening is not available for many cancer types. Even for cancers that have effective screening protocols available, there are barriers to screening in obese individuals, such as reduced mobility and embarrassment. These barriers often delay screening in these vulnerable population groups, leading to detection of the disease at a more advanced stage and ultimately leading to a poorer prognosis. As of today, biomarkers do not replace but augment imaging and other existing screening approaches. Future development of blood- or urine-based biomarkers as a way to screen individuals at high risk for certain cancers may prove to be an excellent method for overcoming the barriers that individuals at high risk are facing today. The overall purpose of this manuscript is to provide an overview of screening techniques and to identified barriers and alternate biomarker-based approaches for improvement of endometrial and breast cancer screening in obese women.

PMID: 22112316 [PubMed - indexed for MEDLINE]

Metastatic invasive breast cancer recurrence following curative-intent therapy for ductal carcinoma in situ.

J Surg Res. 2012 Mar;173(1):10-5

Authors: Al Mushawah F, Rastelli A, Pluard T, Margenthaler JA

Abstract
BACKGROUND: The development of an invasive breast cancer recurrence outside of the breast parenchyma following curative-intent therapy for ductal carcinoma in situ (DCIS) is rare. We describe the patient and tumor characteristics associated with such recurrences.
METHODS: A retrospective review was conducted of 621 patients who were treated for DCIS between 2004 and 2009. Patient, tumor, and treatment characteristics were collected. Descriptive statistics were utilized for data summary and data were compared using χ(2), where appropriate.
RESULTS: Of 621 patients who underwent curative-intent therapy for DCIS, 12 (1.9%) developed an invasive metastatic recurrence. Primary local therapy at the time of the initial DCIS diagnosis included 11 patients who underwent mastectomy and one who had lumpectomy and adjuvant radiotherapy. The metastatic recurrences were in chest wall and/or ipsilateral axillary lymph nodes only (n = 6) or distant sites with or without ipsilateral axillary or supraclavicular lymph nodes (n = 6). Of the 12 patients with invasive recurrence, eight had high grade DCIS with comedo necrosis at initial diagnosis. The biomarker profiles of the invasive recurrences included 55% estrogen receptor positivity, 45% progesterone receptor positivity, and 73% Her2/neu amplification. Patient age, tumor grade, presence of comedo necrosis, biomarker profile, and surgical treatment were not predictive of recurrence.
CONCLUSION: Invasive metastatic recurrence following adequate local therapy for DCIS is uncommon and likely represents progression of unidentified invasive disease at the time of diagnosis. The majority of invasive recurrences were Her2/neu amplified. Further studies are necessary to determine if such a unique biomarker profile correlates with metastatic recurrence.

PMID: 21696764 [PubMed - indexed for MEDLINE]

Epigenetic changes of CXCR4 and its ligand CXCL12 as prognostic factors for sporadic breast cancer.

PLoS One. 2011;6(12):e29461

Authors: Ramos EA, Grochoski M, Braun-Prado K, Seniski GG, Cavalli IJ, Ribeiro EM, Camargo AA, Costa FF, Klassen G

Abstract
Chemokines and their receptors are involved in the development and cancer progression. The chemokine CXCL12 interacts with its receptor, CXCR4, to promote cellular adhesion, survival, proliferation and migration. The CXCR4 gene is upregulated in several types of cancers, including skin, lung, pancreas, brain and breast tumors. In pancreatic cancer and melanoma, CXCR4 expression is regulated by DNA methylation within its promoter region. In this study we examined the role of cytosine methylation in the regulation of CXCR4 expression in breast cancer cell lines and also correlated the methylation pattern with the clinicopathological aspects of sixty-nine primary breast tumors from a cohort of Brazilian women. RT-PCR showed that the PMC-42, MCF7 and MDA-MB-436 breast tumor cell lines expressed high levels of CXCR4. Conversely, the MDA-MB-435 cell line only expressed CXCR4 after treatment with 5-Aza-CdR, which suggests that CXCR4 expression is regulated by DNA methylation. To confirm this hypothesis, a 184 bp fragment of the CXCR4 gene promoter region was cloned after sodium bisulfite DNA treatment. Sequencing data showed that cell lines that expressed CXCR4 had only 15% of methylated CpG dinucleotides, while the cell line that not have CXCR4 expression, had a high density of methylation (91%). Loss of DNA methylation in the CXCR4 promoter was detected in 67% of the breast cancer analyzed. The absence of CXCR4 methylation was associated with the tumor stage, size, histological grade, lymph node status, ESR1 methylation and CXCL12 methylation, metastasis and patient death. Kaplan-Meier curves demonstrated that patients with an unmethylated CXCR4 promoter had a poorer overall survival and disease-free survival. Furthermore, patients with both CXCL12 methylation and unmethylated CXCR4 had a shorter overall survival and disease-free survival. These findings suggest that the DNA methylation status of both CXCR4 and CXCL12 genes could be used as a biomarker for prognosis in breast cancer.

PMID: 22220212 [PubMed - indexed for MEDLINE]

Plasma miR-221 as a predictive biomarker for chemoresistance in breast cancer patients who previously received neoadjuvant chemotherapy.

Onkologie. 2011;34(12):675-80

Authors: Zhao R, Wu J, Jia W, Gong C, Yu F, Ren Z, Chen K, He J, Su F

Abstract
BACKGROUND: Neoadjuvant chemotherapy (NAC) is increasingly being used in breast cancer treatment. Research has revealed an elevated expression of miR-221 in adriamycinresistant MCF-7/ADR cells. This study aimed to explore the potential role of miR-221 as a biomarker for chemosensitivity in breast cancer patients who previously received NAC.
PATIENTS AND METHODS: The expression levels of circulating miR-221 in the plasma of 93 breast cancer patients who previously received NAC and in 32 healthy individuals were assessed. The correlations between miR-221 and clinicopathological features and chemosensitivity were also analysed.
RESULTS: The expression level of miR-221 was significantly associated with hormone receptor (HR) status (p = 0.008). Patients with higher plasma miR-221 levels tended to be HR-negative. Patients with different miR-221 levels had significant differences in the overall response rate (p = 0.044) but not in the pathologic complete response rate (p = 0.477).
CONCLUSION: Our results indicate that plasma miR-221 may be a predictive biomarker for sensitivity to NAC in breast cancer patients.

PMID: 22156446 [PubMed - indexed for MEDLINE]

Discovery of error-tolerant biclusters from noisy gene expression data.

BMC Bioinformatics. 2011;12 Suppl 12:S1

Authors: Gupta R, Rao N, Kumar V

Abstract
BACKGROUND: An important analysis performed on microarray gene-expression data is to discover biclusters, which denote groups of genes that are coherently expressed for a subset of conditions. Various biclustering algorithms have been proposed to find different types of biclusters from these real-valued gene-expression data sets. However, these algorithms suffer from several limitations such as inability to explicitly handle errors/noise in the data; difficulty in discovering small bicliusters due to their top-down approach; inability of some of the approaches to find overlapping biclusters, which is crucial as many genes participate in multiple biological processes. Association pattern mining also produce biclusters as their result and can naturally address some of these limitations. However, traditional association mining only finds exact biclusters, which limits its applicability in real-life data sets where the biclusters may be fragmented due to random noise/errors. Moreover, as they only work with binary or boolean attributes, their application on gene-expression data require transforming real-valued attributes to binary attributes, which often results in loss of information. Many past approaches have tried to address the issue of noise and handling real-valued attributes independently but there is no systematic approach that addresses both of these issues together.
RESULTS: In this paper, we first propose a novel error-tolerant biclustering model, 'ET-bicluster', and then propose a bottom-up heuristic-based mining algorithm to sequentially discover error-tolerant biclusters directly from real-valued gene-expression data. The efficacy of our proposed approach is illustrated by comparing it with a recent approach RAP in the context of two biological problems: discovery of functional modules and discovery of biomarkers. For the first problem, two real-valued S.Cerevisiae microarray gene-expression data sets are used to demonstrate that the biclusters obtained from ET-bicluster approach not only recover larger set of genes as compared to those obtained from RAP approach but also have higher functional coherence as evaluated using the GO-based functional enrichment analysis. The statistical significance of the discovered error-tolerant biclusters as estimated by using two randomization tests, reveal that they are indeed biologically meaningful and statistically significant. For the second problem of biomarker discovery, we used four real-valued Breast Cancer microarray gene-expression data sets and evaluate the biomarkers obtained using MSigDB gene sets.
CONCLUSIONS: The results obtained for both the problems: functional module discovery and biomarkers discovery, clearly signifies the usefulness of the proposed ET-bicluster approach and illustrate the importance of explicitly incorporating noise/errors in discovering coherent groups of genes from gene-expression data.

PMID: 22168285 [PubMed - indexed for MEDLINE]