Publications by authors named "Soonweng Cho"

15 Publications

  • Page 1 of 1

HEYL Regulates Neoangiogenesis Through Overexpression in Both Breast Tumor Epithelium and Endothelium.

Front Oncol 2020 15;10:581459. Epub 2021 Jan 15.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Blocking tumor angiogenesis is an appealing therapeutic strategy, but to date, success has been elusive. We previously identified HEYL, a downstream target of Notch signaling, as an overexpressed gene in both breast cancer cells and as a tumor endothelial marker, suggesting that HEYL overexpression in both compartments may contribute to neoangiogenesis. Carcinomas arising in double transgenic Her2-neu/HeyL mice showed higher tumor vessel density and significantly faster growth than tumors in parental Her2/neu mice. Providing mechanistic insight, microarray-based mRNA profiling of HS578T-tet-off-HEYL human breast cancer cells revealed upregulation of several angiogenic factors including CXCL1/2/3 upon HEYL expression, which was validated by RT-qPCR and protein array analysis. Upregulation of the cytokines CXCL1/2/3 occurred through direct binding of HEYL to their promoter sequences. We found that vessel growth and migration of human vascular endothelial cells (HUVECs) was promoted by conditioned medium from HS578T-tet-off-HEYL carcinoma cells, but was blocked by neutralizing antibodies against CXCL1/2/3. Supporting these findings, suppressing HEYL expression using shRNA in MDA-MB-231 cells significantly reduced tumor growth. In addition, suppressing the action of proangiogenic cytokines induced by HEYL using a small molecule inhibitor of the CXCl1/2/3 receptor, CXCR2, in combination with the anti-VEGF monoclonal antibody, bevacizumab, significantly reduced tumor growth of MDA-MB-231 xenografts. Thus, HEYL expression in tumor epithelium has a profound effect on the vascular microenvironment in promoting neoangiogenesis. Furthermore, we show that lack of HEYL expression in endothelial cells leads to defects in neoangiogenesis, both under normal physiological conditions and in cancer. Thus, HeyL-/- mice showed impaired vessel outgrowth in the neonatal retina, while the growth of mammary tumor cells E0771 was retarded in syngeneic HeyL-/- mice compared to wild type C57/Bl6 mice. Blocking HEYL's angiogenesis-promoting function in both tumor cells and tumor-associated endothelium may enhance efficacy of therapy targeting the tumor vasculature in breast cancer.
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http://dx.doi.org/10.3389/fonc.2020.581459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845423PMC
January 2021

Characterization of an unbalanced translocation causing 3q28qter duplication and 10q26.2qter deletion in a patient with global developmental delay and self-injury.

Cold Spring Harb Mol Case Stud 2020 Dec 17;6(6). Epub 2020 Dec 17.

Program in Human Genetics, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.

Chromosomal structural variation can cause severe neurodevelopmental and neuropsychiatric phenotypes. Here we present a nonverbal female adolescent with severe stereotypic movement disorder with severe problem behavior (e.g., self-injurious behavior, aggression, and disruptive and destructive behaviors), autism spectrum disorder, severe intellectual disability, attention deficit hyperactivity disorder, and global developmental delay. Previous cytogenetic analysis revealed balanced translocations present in the patient's apparently normal mother. We hypothesized the presence of unbalanced translocations in the patient due to maternal history of spontaneous abortions. Whole-genome sequencing and whole-genome optical mapping, complementary next-generation genomic technologies capable of the accurate and robust detection of structural variants, identified t(3;10), t(10;14), and t(3;14) three-way balanced translocations in the mother and der(10)t(3;14;10) and der(14)t(3;14;10) translocations in the patient. Instead of a t(3;10), she inherited a normal maternal copy of Chromosome 3, resulting in an unbalanced state of a 3q28qter duplication and 10q26.2qter deletion. Copy-imbalanced genes in one or both of these regions, such as , , and , may contribute to the patient's phenotype that spans neurodevelopmental, musculoskeletal, and psychiatric domains, with the possible contribution of a maternally inherited 15q13.2q13.3 deletion.
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http://dx.doi.org/10.1101/mcs.a005884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784495PMC
December 2020

DNA methylation markers predict recurrence-free interval in triple-negative breast cancer.

NPJ Breast Cancer 2020 31;6. Epub 2020 Jan 31.

1Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA.

We lack tools to risk-stratify triple-negative breast cancer (TNBC). Our goal was to develop molecular tools to predict disease recurrence. Methylation array analysis was performed on 110 samples treated by locoregional therapy obtained from institutional cohorts. Discovered marker sets were then tested by Kaplan-Meier analyses in a prospectively collected TNBC cohort of 49 samples from the no-chemotherapy arms of IBCSG trials VIII and IX, and by logistic regression in a chemotherapy-treated cohort of 121 TNBCs from combined IBCSG trials and institutional repositories. High methylation was associated with shorter recurrence-free interval in the no-chemotherapy arm of the IBCSG studies, as well as in the chemotherapy-treated patients within the combined institutional and IBCSG chemotherapy cohorts (100 marker panel,  = 0.002; 30 marker panel,  = 0.05). Chromosome 19 sites were enriched among these loci. In conclusion, our hypermethylation signatures identify increased recurrence risk independent of whether patients receive chemotherapy.
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http://dx.doi.org/10.1038/s41523-020-0145-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994477PMC
January 2020

Sturge-Weber Syndrome Patient Registry: Delayed Diagnosis and Poor Seizure Control.

J Pediatr 2019 12 3;215:158-163.e6. Epub 2019 Oct 3.

Department of Neurology, Kennedy Krieger Institute, Baltimore, MD; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD; The Sturge-Weber Foundation, Houston, TX. Electronic address:

Objective: To examine the symptomatology and treatment of Sturge-Weber syndrome (SWS) from a large patient registry to identify common symptoms, clinical outcomes, and areas of unmet clinical need.

Study Design: An online patient questionnaire was completed by 628 patients with clinically diagnosed SWS and/or a port-wine birthmark over a 19-year period. Statistical analysis focused on seizures as a primary outcome measure, as well as associated neurologic, ophthalmologic, and dermatologic attributes to understand some of the natural history of the disorder.

Results: The majority (92%) of patients had a port-wine birthmark, and 60% of the patients had neurologic symptoms, including seizures and stroke-like episodes. Glaucoma was present in 48% of the patients. Other common symptoms included behavioral (46%) and hearing (or vestibular) disorders (24%). Delayed diagnosis of SWS beyond 1 year after presentation of initial symptoms occurred in 16% of the patients, with 68% having clear preexisting comorbidities, especially headaches. Birthmarks on the forehead and scalp were associated with seizures (P < .001), whereas bilaterality of birthmarks was not. Only 49% of patients being treated for epilepsy were free of seizures.

Conclusions: Seizures and glaucoma were the primary drivers for a diagnosis of SWS in patients with delayed diagnosis, and hearing (or vestibular) and behavioral problems were also prevalent. The diagnosis of SWS was delayed when the predominant symptom was headache. Seizure control was quite poor in many patients with SWS. Our findings highlight an important need for detailed, longitudinal data to improve our understanding of SWS and develop better treatment strategies for patients with this disorder.
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http://dx.doi.org/10.1016/j.jpeds.2019.08.025DOI Listing
December 2019

Measuring DNA Copy Number Variation Using High-Density Methylation Microarrays.

J Comput Biol 2019 04 21;26(4):295-304. Epub 2019 Feb 21.

5 Department of Oncology Bioinformatics, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

Genetic and epigenetic changes drive carcinogenesis, and their integrated analysis provides insights into mechanisms of cancer development. Computational methods have been developed to measure copy number variation (CNV) from methylation array data, including ChAMP-CNV, CN450K, and, introduced here, Epicopy. Using paired single nucleotide polymorphism (SNP) and methylation array data from the public The Cancer Genome Atlas repository, we optimized CNV calling and benchmarked the performance of these methods. We optimized the thresholds of all three methods and showed comparable performance across methods. Using Epicopy as a representative analysis of Illumina450K array, we show that Illumina450K-derived CNV methods achieve a sensitivity of 0.7 and a positive predictive value of 0.75 in identifying CNVs, which is similar to results achieved when comparing competing SNP microarray platforms with each other.
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http://dx.doi.org/10.1089/cmb.2018.0143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479247PMC
April 2019

Induction of cell cycle arrest and inflammatory genes by combined treatment with epigenetic, differentiating, and chemotherapeutic agents in triple-negative breast cancer.

Breast Cancer Res 2018 11 28;20(1):145. Epub 2018 Nov 28.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: A combination of entinostat, all-trans retinoic acid, and doxorubicin (EAD) induces cell death and differentiation and causes significant regression of xenografts of triple-negative breast cancer (TNBC).

Methods: We investigated the mechanisms underlying the antitumor effects of each component of the EAD combination therapy by high-throughput gene expression profiling of drug-treated cells.

Results: Microarray analysis showed that entinostat and doxorubicin (ED) altered expression of genes related to growth arrest, inflammation, and differentiation. ED downregulated MYC, E2F, and G2M cell cycle genes. Accordingly, entinostat sensitized the cells to doxorubicin-induced growth arrest at G2. ED induced interferon genes, which correlated with breast tumors containing a higher proportion of tumor-infiltrating lymphocytes. ED also increased the expression of immune checkpoint agonists and cancer testis antigens. Analysis of TNBC xenografts showed that EAD enhanced the inflammation score in nude mice. Among the genes differentially regulated between the EAD and ED groups, an all-trans retinoic acid (ATRA)-regulated gene, DHRS3, was induced in EAD-treated xenografts. DHRS3 was expressed at lower levels in human TNBC metastases compared to normal breast or primary tumors. High expression of ED-induced growth arrest and inflammatory genes was associated with better prognosis in TNBC patients.

Conclusions: Entinostat potentiated doxorubicin-mediated cell death and the combination induced inflammatory signatures. The ED-induced immunomodulation may improve immunotherapy. Addition of ATRA to ED may potentiate inflammation and contribute to TNBC regression.
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http://dx.doi.org/10.1186/s13058-018-1068-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263070PMC
November 2018

Multi-omics profiling of younger Asian breast cancers reveals distinctive molecular signatures.

Nat Commun 2018 04 30;9(1):1725. Epub 2018 Apr 30.

Samsung Biological Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea.

Breast cancer (BC) in the Asia Pacific regions is enriched in younger patients and rapidly rising in incidence yet its molecular bases remain poorly characterized. Here we analyze the whole exomes and transcriptomes of 187 primary tumors from a Korean BC cohort (SMC) enriched in pre-menopausal patients and perform systematic comparison with a primarily Caucasian and post-menopausal BC cohort (TCGA). SMC harbors higher proportions of HER2+ and Luminal B subtypes, lower proportion of Luminal A with decreased ESR1 expression compared to TCGA. We also observe increased mutation prevalence affecting BRCA1, BRCA2, and TP53 in SMC with an enrichment of a mutation signature linked to homologous recombination repair deficiency in TNBC. Finally, virtual microdissection and multivariate analyses reveal that Korean BC status is independently associated with increased TIL and decreased TGF-β signaling expression signatures, suggesting that younger Asian BCs harbor more immune-active microenvironment than western BCs.
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http://dx.doi.org/10.1038/s41467-018-04129-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928087PMC
April 2018

Inhibitors of STAT3, β-catenin, and IGF-1R sensitize mouse PIK3CA-mutant breast cancer to PI3K inhibitors.

Mol Oncol 2017 05 6;11(5):552-566. Epub 2017 Apr 6.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Although mutations in the phosphoinositide 3-kinase catalytic subunit (PIK3CA) are common in breast cancer, PI3K inhibitors alone have shown modest efficacy. We sought to identify additional pathways altered in PIK3CA-mutant tumors that might be targeted in combination with PI3K inhibitors. We generated two transgenic mouse models expressing the human PIK3CA-H1047R- and the -E545K hotspot-mutant genes in the mammary gland and evaluated their effects on development and tumor formation. Molecular analysis identified pathways altered in these mutant tumors, which were also targeted in multiple cell lines derived from the PIK3CA tumors. Finally, public databases were analyzed to determine whether novel pathways identified in the mouse tumors were altered in human tumors harboring mutant PIK3CA. Mutant mice showed increased branching and delayed involution of the mammary gland compared to parental FVB/N mice. Mammary tumors arose in 30% of the MMTV-PIK3CA-H1047R and in 13% of -E545K mice. Compared to MMTV-Her-2 transgenic mouse mammary tumors, H1047R tumors showed increased upregulation of Wnt/β-catenin/Axin2, hepatocyte growth factor (Hgf)/Stat3, insulin-like growth factor 2 (Igf-2), and Igf-1R pathways. Inhibitors of STAT3, β-catenin, and IGF-1R sensitized H1047R-derived mouse tumor cells and PIK3CA-H1047R overexpressing human HS578T breast cancer cells to the cytotoxic effects of PI3K inhibitors. Analysis of The Cancer Genome Atlas database showed that, unlike primary PIK3CA-wild-type and HER-2 breast carcinomas, PIK3CA-mutant tumors display increased expression of AXIN2, HGF, STAT3, IGF-1, and IGF-2 mRNA and activation of AKT, IGF1-MTOR, and WNT canonical signaling pathways. Drugs targeting additional pathways that are altered in PIK3CA-mutant tumors may improve treatment regimens using PI3K inhibitors alone.
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http://dx.doi.org/10.1002/1878-0261.12053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527464PMC
May 2017

Optimizing the Use of Gene Expression Profiling in Early-Stage Breast Cancer.

J Clin Oncol 2016 12 31;34(36):4390-4397. Epub 2016 Oct 31.

Hyun-seok Kim, Christopher B. Umbricht, Peter B. Illei, Ashley Cimino-Mathews, Soonweng Cho, Nivedita Chowdhury, Maria Cristina Figueroa-Magalhaes, Catherine Pesce, Stacie C. Jeter, Deborah K. Armstrong, Roisin M. Connolly, John H. Fetting, Ben Ho Park, Vered Stearns, Antonio C. Wolff, and Leslie Cope, The Johns Hopkins University School of Medicine; Kala Visvanathan, The Johns Hopkins University Bloomberg School of Public Health, Baltimore; Charles Mylander, Martin Rosman, and Lorraine Tafra, Anne Arundel Medical Center, Annapolis, MD; Bradley M. Turner, David G. Hicks, University of Rochester Medical Center, Rochester, NY; Robert S. Miller, American Society of Clinical Oncology, Alexandria, VA; and Tyler A. Jensen and Dylan V. Miller, Intermountain Healthcare, Salt Lake City, UT.

Purpose Gene expression profiling assays are frequently used to guide adjuvant chemotherapy decisions in hormone receptor-positive, lymph node-negative breast cancer. We hypothesized that the clinical value of these new tools would be more fully realized when appropriately integrated with high-quality clinicopathologic data. Hence, we developed a model that uses routine pathologic parameters to estimate Oncotype DX recurrence score (ODX RS) and independently tested its ability to predict ODX RS in clinical samples. Patients and Methods We retrospectively reviewed ordered ODX RS and pathology reports from five institutions (n = 1,113) between 2006 and 2013. We used locally performed histopathologic markers (estrogen receptor, progesterone receptor, Ki-67, human epidermal growth factor receptor 2, and Elston grade) to develop models that predict RS-based risk categories. Ordering patterns at one site were evaluated under an integrated decision-making model incorporating clinical treatment guidelines, immunohistochemistry markers, and ODX. Final locked models were independently tested (n = 472). Results Distribution of RS was similar across sites and to reported clinical practice experience and stable over time. Histopathologic markers alone determined risk category with > 95% confidence in > 55% (616 of 1,113) of cases. Application of the integrated decision model to one site indicated that the frequency of testing would not have changed overall, although ordering patterns would have changed substantially with less testing of estimated clinical risk-high or clinical risk-low cases and more testing of clinical risk-intermediate cases. In the validation set, the model correctly predicted risk category in 52.5% (248 of 472). Conclusion The proposed model accurately predicts high- and low-risk RS categories (> 25 or ≤ 25) in a majority of cases. Integrating histopathologic and molecular information into the decision-making process allows refocusing the use of new molecular tools to cases with uncertain risk.
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http://dx.doi.org/10.1200/JCO.2016.67.7195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455310PMC
December 2016

Association of BRAF V600E Mutation and MicroRNA Expression with Central Lymph Node Metastases in Papillary Thyroid Cancer: A Prospective Study from Four Endocrine Surgery Centers.

Thyroid 2016 Apr 7;26(4):532-42. Epub 2016 Mar 7.

1 Endocrine Surgery, Department of Surgery, The Johns Hopkins University School of Medicine , Baltimore, Maryland.

Background: Studies have demonstrated an association of the BRAF(V600E) mutation and microRNA (miR) expression with aggressive clinicopathologic features in papillary thyroid cancer (PTC). Analysis of BRAF(V600E) mutations with miR expression data may improve perioperative decision making for patients with PTC, specifically in identifying patients harboring central lymph node metastases (CLNM).

Methods: Between January 2012 and June 2013, 237 consecutive patients underwent total thyroidectomy and prophylactic central lymph node dissection (CLND) at four endocrine surgery centers. All tumors were tested for the presence of the BRAF(V600E) mutation and miR-21, miR-146b-3p, miR-146b-5p, miR-204, miR-221, miR-222, and miR-375 expression. Bivariate and multivariable analyses were performed to examine associations between molecular markers and aggressive clinicopathologic features of PTC.

Results: Multivariable logistic regression analysis of all clinicopathologic features found miR-146b-3p and miR-146b-5p to be independent predictors of CLNM, while the presence of BRAF(V600E) almost reached significance. Multivariable logistic regression analysis limited to only predictors available preoperatively (molecular markers, age, sex, and tumor size) found miR-146b-3p, miR-146b-5p, miR-222, and BRAF(V600E) mutation to predict CLNM independently. While BRAF(V600E) was found to be associated with CLNM (48% mutated in node-positive cases vs. 28% mutated in node-negative cases), its positive and negative predictive values (48% and 72%, respectively) limit its clinical utility as a stand-alone marker. In the subgroup analysis focusing on only classical variant of PTC cases (CVPTC), undergoing prophylactic lymph node dissection, multivariable logistic regression analysis found only miR-146b-5p and miR-222 to be independent predictors of CLNM, while BRAF(V600E) was not significantly associated with CLNM.

Conclusion: In the patients undergoing prophylactic CLNDs, miR-146b-3p, miR-146b-5p, and miR-222 were found to be predictive of CLNM preoperatively. However, there was significant overlap in expression of these miRs in the two outcome groups. The BRAF(V600E) mutation, while being a marker of CLNM when considering only preoperative variables among all histological subtypes, is likely not a useful stand-alone marker clinically because the difference between node-positive and node-negative cases was small. Furthermore, it lost significance when examining only CVPTC. Overall, our results speak to the concept and interpretation of statistical significance versus actual applicability of molecular markers, raising questions about their clinical usefulness as individual prognostic markers.
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http://dx.doi.org/10.1089/thy.2015.0378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827320PMC
April 2016

Combined Treatment with Epigenetic, Differentiating, and Chemotherapeutic Agents Cooperatively Targets Tumor-Initiating Cells in Triple-Negative Breast Cancer.

Cancer Res 2016 04 19;76(7):2013-2024. Epub 2016 Jan 19.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Efforts to induce the differentiation of cancer stem cells through treatment with all-trans retinoic acid (ATRA) have yielded limited success, partially due to the epigenetic silencing of the retinoic acid receptor (RAR)-β The histone deacetylase inhibitor entinostat is emerging as a promising antitumor agent when added to the standard-of-care treatment for breast cancer. However, the combination of epigenetic, cellular differentiation, and chemotherapeutic approaches against triple-negative breast cancer (TNBC) has not been investigated. In this study, we found that combined treatment of TNBC xenografts with entinostat, ATRA, and doxorubicin (EAD) resulted in significant tumor regression and restoration of epigenetically silenced RAR-β expression. Entinostat and doxorubicin treatment inhibited topoisomerase II-β (TopoII-β) and relieved TopoII-β-mediated transcriptional silencing of RAR-β Notably, EAD was the most effective combination in inducing differentiation of breast tumor-initiating cells in vivo Furthermore, gene expression analysis revealed that the epithelium-specific ETS transcription factor-1 (ESE-1 or ELF3), known to regulate proliferation and differentiation, enhanced cell differentiation in response to EAD triple therapy. Finally, we demonstrate that patient-derived metastatic cells also responded to treatment with EAD. Collectively, our findings strongly suggest that entinostat potentiates doxorubicin-mediated cytotoxicity and retinoid-driven differentiation to achieve significant tumor regression in TNBC. Cancer Res; 76(7); 2013-24. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-1619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873448PMC
April 2016

Subtype-specific overexpression of the Rac-GEF P-REX1 in breast cancer is associated with promoter hypomethylation.

Breast Cancer Res 2014 Sep 24;16(5):441. Epub 2014 Sep 24.

Introduction: The Rac-GEF P-REX1 is a key mediator of ErbB signaling in breast cancer recently implicated in mammary tumorigenesis and metastatic dissemination. Although P-REX1 is essentially undetectable in normal human mammary epithelial tissue, this Rac-GEF is markedly upregulated in human breast carcinomas, particularly of the luminal subtype. The mechanisms underlying P-REX1 upregulation in breast cancer are unknown. Toward the goal of dissecting the mechanistic basis of P-REX1 overexpression in breast cancer, in this study we focused on the analysis of methylation of the PREX1 gene promoter.

Methods: To determine the methylation status of the PREX1 promoter region, we used bisulfite genomic sequencing and pyrosequencing approaches. Re-expression studies in cell lines were carried out by treatment of breast cancer cells with the demethylating agent 5-aza-2'-deoxycitidine. PREX1 gene methylation in different human breast cancer subtypes was analyzed from the TCGA database.

Results: We found that the human PREX1 gene promoter has a CpG island located between -1.2 kb and +1.4 kb, and that DNA methylation in this region inversely correlates with P-REX1 expression in human breast cancer cell lines. A comprehensive analysis of human breast cancer cell lines and tumors revealed significant hypomethylation of the PREX1 promoter in ER-positive, luminal subtype, whereas hypermethylation occurs in basal-like breast cancer. Treatment of normal MCF-10A or basal-like cancer cells, MDA-MB-231 with the demethylating agent 5-aza-2'-deoxycitidine in combination with the histone deacetylase inhibitor trichostatin A restores P-REX1 levels to those observed in luminal breast cancer cell lines, suggesting that aberrant expression of P-REX1 in luminal breast cancer is a consequence of PREX1 promoter demethylation. Unlike PREX1, the pro-metastatic Rho/Rac-GEF, VAV3, is not regulated by methylation. Notably, PREX1 gene promoter hypomethylation is a prognostic marker of poor patient survival.

Conclusions: Our study identified for the first time gene promoter hypomethylation as a distinctive subtype-specific mechanism for controlling the expression of a key regulator of Rac-mediated motility and metastasis in breast cancer.
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http://dx.doi.org/10.1186/s13058-014-0441-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303123PMC
September 2014

The Notch pathway inhibits TGFβ signaling in breast cancer through HEYL-mediated crosstalk.

Cancer Res 2014 Nov 12;74(22):6509-18. Epub 2014 Sep 12.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Acquired resistance to TGFβ is a key step in the early stages of tumorigenesis. Mutations in TGFβ signaling components are rare, and little is known about the development of resistance in breast cancer. On the other hand, an activated Notch pathway is known to play a substantial role in promoting breast cancer development. Here, we present evidence of crosstalk between these two pathways through HEYL. HEYL, a basic helix-loop-helix transcription factor and a direct target of Notch signaling, is specifically overexpressed in breast cancer. HEYL represses TGFβ activity by binding to TGFβ-activated Smads. HeyL(-/-) mice have defective mammary gland development with fewer terminal end buds. On the other hand, HeyL transgenic mice show accelerated mammary gland epithelial proliferation and 24% of multiparous mice develop mammary gland cancer. Therefore, repression of TGFβ signaling by Notch acting through HEYL may promote initiation of breast cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-0816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4233182PMC
November 2014

Novel methylated biomarkers and a robust assay to detect circulating tumor DNA in metastatic breast cancer.

Cancer Res 2014 Apr;74(8):2160-70

Authors' Affiliations: Departments of Oncology, Surgery, and Surgical Pathology, Johns Hopkins University School of Medicine; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore Maryland; Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York; Departments of Oncology and Surgery, Mayo Clinic, Rochester, Minnesota; Department of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina.

The ability to consistently detect cell-free tumor-specific DNA in peripheral blood of patients with metastatic breast cancer provides the opportunity to detect changes in tumor burden and to monitor response to treatment. We developed cMethDNA, a quantitative multiplexed methylation-specific PCR assay for a panel of ten genes, consisting of novel and known breast cancer hypermethylated markers identified by mining our previously reported study of DNA methylation patterns in breast tissue (103 cancer, 21 normal on the Illumina HumanMethylation27 Beadchip) and then validating the 10-gene panel in The Cancer Genome Atlas project breast cancer methylome database. For cMethDNA, a fixed physiologic level (50 copies) of artificially constructed, standard nonhuman reference DNA specific for each gene is introduced in a constant volume of serum (300 μL) before purification of the DNA, facilitating a sensitive, specific, robust, and quantitative assay of tumor DNA, with broad dynamic range. Cancer-specific methylated DNA was detected in training (28 normal, 24 cancer) and test (27 normal, 33 cancer) sets of recurrent stage IV patient sera with a sensitivity of 91% and a specificity of 96% in the test set. In a pilot study, cMethDNA assay faithfully reflected patient response to chemotherapy (N = 29). A core methylation signature present in the primary breast cancer was retained in serum and metastatic tissues collected at autopsy two to 11 years after diagnosis of the disease. Together, our data suggest that the cMethDNA assay can detect advanced breast cancer, and monitor tumor burden and treatment response in women with metastatic breast cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-13-3392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4327879PMC
April 2014

HOXB13 mediates tamoxifen resistance and invasiveness in human breast cancer by suppressing ERα and inducing IL-6 expression.

Cancer Res 2013 Sep 5;73(17):5449-58. Epub 2013 Jul 5.

Departments of Oncology, Surgery, and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231-1000, USA.

Most breast cancers expressing the estrogen receptor α (ERα) are treated successfully with the receptor antagonist tamoxifen (TAM), but many of these tumors recur. Elevated expression of the homeodomain transcription factor HOXB13 correlates with TAM-resistance in ERα-positive (ER+) breast cancer, but little is known regarding the underlying mechanism. Our comprehensive evaluation of HOX gene expression using tiling microarrays, with validation, showed that distant metastases from TAM-resistant patients also displayed high HOXB13 expression, suggesting a role for HOXB13 in tumor dissemination and survival. Here we show that HOXB13 confers TAM resistance by directly downregulating ERα transcription and protein expression. HOXB13 elevation promoted cell proliferation in vitro and growth of tumor xenografts in vivo. Mechanistic investigations showed that HOXB13 transcriptionally upregulated interleukin (IL)-6, activating the mTOR pathway via STAT3 phosphorylation to promote cell proliferation and fibroblast recruitment. Accordingly, mTOR inhibition suppressed fibroblast recruitment and proliferation of HOXB13-expressing ER+ breast cancer cells and tumor xenografts, alone or in combination with TAM. Taken together, our results establish a function for HOXB13 in TAM resistance through direct suppression of ERα and they identify the IL-6 pathways as mediator of disease progression and recurrence.
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http://dx.doi.org/10.1158/0008-5472.CAN-13-1178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967590PMC
September 2013