Association of hypoxia-induced centrosome amplification with clinical outcomes in triple-negative breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23170-e23170
Author(s):  
Karuna Mittal ◽  
Da Hoon Choi ◽  
Angela Ogden ◽  
Brian D Melton ◽  
Meenakshi Vij Gupta ◽  
...  
Keyword(s):  
Gene Expression ◽  
Triple Negative ◽  
Gene Expression Signature ◽  
Breast Tumors ◽  
Centrosome Amplification ◽  
Strong Positive Correlation ◽  
Breast Cancers ◽  
Tissue Samples ◽  
Hypoxic Conditions ◽  
Cells Cultured

e23170 Background: Centrosome amplification (CA) which refers to presence of supernumerary or abnormally large centrosomes is believed to drive tumor progression by promoting chromosomal instability and the generation of aggressive tumor clones that are more capable of rapid metastasis. Not much is known about factors that drive CA within solid tumors. We have previously shown the existence of rampant CA in triple-negative breast cancers (TNBCs).We report here thatintratumoral hypoxia, which is one of the major contributors to tumor heterogeneity, induces CA in TNBCs via HIF-1α. Methods: We immunohistochemically labeled 24 TNBC and adjacent normal tissue samples for HIF-1α and derived weighted indices (WIs) for nuclear HIF-1α. Adjacent serial sections from the same tumors were immunofluorescently labeled for the centrosomal marker γ-tubulin and CA was determined. Using public microarray datasets (Kao dataset, n = 327), we investigated whether centrosomal gene expression is enriched in breast tumors characterized by a hypoxia gene expression signature. Finally, to test the role of hypoxia in CA induction we exposed cultured TNBC cells (MDA-MB-231 and MDA-MB-468) to hypoxia and overexpressed (OE) or knocked out (KO) HIF-1α and quantitated CA. Results: A strong positive correlation was found between nuclear HIF-1α WI and CA in TNBC samples (Spearman’s rho p = 0.722, p < 0.001), and higher nuclear HIF-1α was associated with worse overall survival (p = 0.041; HR = 1.03). Furthermore, breast tumors with high expression of hypoxia-associated genes exhibited higher expression of centrosomal genes than breast tumors with low expression of hypoxia-associated genes. TNBC cells cultured in hypoxic conditions exhibited ~1.5 fold higher (p < 0.05) CA compared to cells cultured in normoxic conditions. Interestingly, level of CA decreased when HIF-1α KO TNBC cells were exposed to hypoxia; conversely, CA increased when HIF-1α OE TNBC cells were cultured in normoxic conditions. Conclusions: Thus,intratumoral hypoxia drives CA in TNBC via HIF-1α and contributes to poor outcomes. Determination of CA may help identify TNBC patients who could benefit from centrosome declustering drugs and HIF-1α inhibitors.

scholarly journals High incidence of triple negative breast cancers following pregnancy and an associated gene expression signature

SpringerPlus ◽  
2015 ◽  
Vol 4 (1) ◽  
Author(s):  
Szilard Asztalos ◽  
Thao N. Pham ◽  
Peter H. Gann ◽  
Meghan K. Hayes ◽  
Ryan Deaton ◽  
...  
Keyword(s):  
Gene Expression ◽  
Triple Negative ◽  
Gene Expression Signature ◽  
Breast Cancers ◽  
Expression Signature ◽  
High Incidence

Abstract SS1-07: Gene expression profiles of Ghanaian and Ethiopian triple-negative breast tumors

2021 ◽  
Author(s):  
Rachel Martini ◽  
Endale Gebregzabher ◽  
Princesca Dorsaint ◽  
Timothy Chu ◽  
Kanika Arora ◽  
...  
Keyword(s):  
Gene Expression ◽  
Triple Negative ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Breast Tumors

scholarly journals Gene expression profiling of triple-negative breast tumors with different expression of secreted protein acidic and cysteine rich (SPARC)

2018 ◽  
Vol 7 (2) ◽  
pp. BMT09
Author(s):  
Paulo R de Alcantara Filho ◽  
Flavia R Mangone ◽  
Ana C Pavanelli ◽  
Simone A de Bessa Garcia ◽  
Suely Nonogaki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Triple Negative ◽  
Breast Tumors ◽  
Secreted Protein

scholarly journals Pan-cancer association of a centrosome amplification gene expression signature with genomic alterations and clinical outcome

2019 ◽  
Vol 15 (3) ◽  
pp. e1006832 ◽  
Author(s):  
Bernardo P. de Almeida ◽  
André F. Vieira ◽  
Joana Paredes ◽  
Mónica Bettencourt-Dias ◽  
Nuno L. Barbosa-Morais
Keyword(s):  
Gene Expression ◽  
Clinical Outcome ◽  
Gene Expression Signature ◽  
Centrosome Amplification ◽  
Genomic Alterations ◽  
Expression Signature ◽  
Pan Cancer

FOXA1 in breast cancer

2009 ◽  
Vol 11 ◽  
Author(s):  
Harikrishna Nakshatri ◽  
Sunil Badve
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Transcription Factor ◽  
Expression Patterns ◽  
Gene Expression Pattern ◽  
Gene Expression Signature ◽  
Specific Gene ◽  
Breast Cancers ◽  
Transcription Factor Network ◽  
Histopathological Classification

Breast cancer is a heterogeneous disease and classification is important for clinical management. At least five subtypes can be identified based on unique gene expression patterns; this subtype classification is distinct from the histopathological classification. The transcription factor network(s) required for the specific gene expression signature in each of these subtypes is currently being elucidated. The transcription factor network composed of the oestrogen (estrogen) receptor α (ERα), FOXA1 and GATA3 may control the gene expression pattern in luminal subtype A breast cancers. Breast cancers that are dependent on this network correspond to well-differentiated and hormone-therapy-responsive tumours with good prognosis. In this review, we discuss the interplay between these transcription factors with a particular emphasis on FOXA1 structure and function, and its ability to control ERα function. Additionally, we discuss modulators of FOXA1 function, ERα–FOXA1–GATA3 downstream targets, and potential therapeutic agents that may increase differentiation through FOXA1.

Characteristic Genes in Luminal Subtype Breast Tumors with CD44+CD24–/Low Gene Expression Signature

Oncology ◽  
2011 ◽  
Vol 81 (5-6) ◽  
pp. 336-344 ◽  
Author(s):  
Y. Tsunoda ◽  
M. Sakamoto ◽  
T. Sawada ◽  
A. Sasaki ◽  
G. Yamamoto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Signature ◽  
Breast Tumors ◽  
Luminal Subtype ◽  
Expression Signature

scholarly journals Identification of Gene Expression Signature in Estrogen Receptor Positive Breast Carcinoma

2010 ◽  
Vol 2 ◽  
pp. BIC.S3793 ◽  
Author(s):  
Arvind D. Thakkar ◽  
Hemanth Raj ◽  
Debarshi Chakrabarti ◽  
Ravishankar ◽  
N. Saravanan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Transcription Factor ◽  
Molecular Basis ◽  
Clinical Specimen ◽  
Gene Expression Signature ◽  
Breast Tumors ◽  
Significant Group ◽  
Six Genes

A significant group of patient with estrogen receptor (ER) α positive breast tumors fails to appreciably respond to endocrine therapy. An increased understanding of the molecular basis of estrogen-mediated signal transduction and resultant gene expression may lead to novel strategies for treating breast cancer. In this study, we sought to identify the dysregulated genes in breast tumors related to ERα status. Microarray analyses of 31 tumor samples showed 108 genes differentially expressed in ERα (+) and ERα (–) primary breast tumors. Further analyses of gene lists indicated that a significant number of dysregulated genes were involved in mRNA transcription and cellular differentiation. The majority of these genes were found to have promoter-binding sites for E74-like factor 5 (ELF5; 54.6% genes), E2F transcription factor 1 (E2F1; 22.2% genes), and nuclear transcription factor Y alpha (NFYA; 32.4% genes). Six candidate genes ( NTN4, SLC7A8, MLPH, ENPP1, LAMB2, and PLAT) with differential expression were selected for further validation studies using RT-qPCR (76 clinical specimen) and immunohistochemistry (48 clinical specimen). Our studies indicate significant overexpression of all the six genes in ERα (+) breast tumors as compared to ERα (–) breast tumors. In vitro studies using T-47D breast cancer cell line confirmed the estrogen dependant expression of four of the above six genes ( SLC7A8, ENPP1, LAMB2, and PLAT). Collectively, our study provides further insights into the molecular basis of estrogen-dependent breast cancer and identifies “candidate biomarkers” that could be useful for predicting endocrine responsiveness.

Genotypic characterization of phenotypically defined triple-negative breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 500-500 ◽  
Author(s):  
J. A. Sparano ◽  
L. J. Goldestin ◽  
B. H. Childs ◽  
S. Shak ◽  
S. Badve ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Triple Negative Breast Cancer ◽  
Intracellular Signaling ◽  
Triple Negative ◽  
Phenotypic Characterization ◽  
Breast Cancers ◽  
Nucleosome Assembly ◽  
Expression Of Genes ◽  
Cancer Phenotypes

500 Background: Triple negative breast cancer (TNBC) is associated with a higher risk of recurrence and earlier recurrences than other breast cancer phenotypes. We evaluated the genotypic features of TNBC compared with hormone receptor (HR)-positive disease, and also evaluated genotypic features associated with recurrence. Methods: RNA extracted from tumor samples obtained from 764 patients with stage I-III breast cancer was analyzed by RT-PCR for 371 genes. All patients received adjuvant chemotherapy (plus hormonal therapy in HR-positive disease) in trial E2197; HR and HER2 expression were evaluated by immunohistochemistry (IHC) in a central lab (J Clin Oncol 26:2473–2481). An unsupervised clustering analysis was performed in all samples (N=764). Cox proportional hazard models were used to identify differences in gene expression in TNBC versus HR-positive disease, and with recurrence in phenotypically defined (by IHC) TNBC (N=246) and HR-positive (N=465) disease. Results: Unsupervised analysis revealed two major clusters that differed with regard to HR expression by IHC. Supervised analysis comparing the TNBC vs. HR-positive phenotypes revealed 269 genes (73%) with significantly different expression (p<0.0001). The top 10% of genes exhibiting higher expression the TN group included genes associated with nucleosome assembly (CENPA), kinase activity (TTK), cell division (KIFC2), proliferation (BUB1), intracellular signaling (DEPDC1), DNA repair (CHK1), anti-apoptosis (GSTP1), and transcriptional regulation (MYBL2). There was increased expression of genes for which inhibitors are currently being evaluated, including AURKB and CHK1 in TNBC, and IGF1R and RhoC in HR-positive disease. Although GRB7 expression was significantly lower in the TN group, increased expression of GRB7 was the only gene in the TNBC group (but not the HR-positive group) associated with increased recurrence (p=0.04), and did not correlate with nodal status, tumor size, or grade. Conclusions: We genotypically characterized breast cancers that have also undergone rigorous phenotypic characterization.. There were significant differences in gene expression between the TN and HR-positive groups, including genes for which targeted agents are currently being evaluated in the clinic. [Table: see text]

scholarly journals Interferon-beta represses cancer stem cell properties in triple-negative breast cancer

2017 ◽  
Vol 114 (52) ◽  
pp. 13792-13797 ◽  
Author(s):  
Mary R. Doherty ◽  
HyeonJoo Cheon ◽  
Damian J. Junk ◽  
Shaveta Vinayak ◽  
Vinay Varadan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Triple Negative Breast Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Triple Negative ◽  
Mammary Epithelial Cells ◽  
Gene Expression Signature ◽  
Tumor Infiltrating Lymphocytes ◽  
Gene Signature ◽  
Mesenchymal Transition

Triple-negative breast cancer (TNBC), the deadliest form of this disease, lacks a targeted therapy. TNBC tumors that fail to respond to chemotherapy are characterized by a repressed IFN/signal transducer and activator of transcription (IFN/STAT) gene signature and are often enriched for cancer stem cells (CSCs). We have found that human mammary epithelial cells that undergo an epithelial-to-mesenchymal transition (EMT) following transformation acquire CSC properties. These mesenchymal/CSCs have a significantly repressed IFN/STAT gene expression signature and an enhanced ability to migrate and form tumor spheres. Treatment with IFN-beta (IFN-β) led to a less aggressive epithelial/non–CSC-like state, with repressed expression of mesenchymal proteins (VIMENTIN, SLUG), reduced migration and tumor sphere formation, and reexpression of CD24 (a surface marker for non-CSCs), concomitant with an epithelium-like morphology. The CSC-like properties were correlated with high levels of unphosphorylated IFN-stimulated gene factor 3 (U-ISGF3), which was previously linked to resistance to DNA damage. Inhibiting the expression of IRF9 (the DNA-binding component of U-ISGF3) reduced the migration of mesenchymal/CSCs. Here we report a positive translational role for IFN-β, as gene expression profiling of patient-derived TNBC tumors demonstrates that an IFN-β metagene signature correlates with improved patient survival, an immune response linked with tumor-infiltrating lymphocytes (TILs), and a repressed CSC metagene signature. Taken together, our findings indicate that repressed IFN signaling in TNBCs with CSC-like properties is due to high levels of U-ISGF3 and that treatment with IFN-β reduces CSC properties, suggesting a therapeutic strategy to treat drug-resistant, highly aggressive TNBC tumors.

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